Comprehensive Physiology Wiley Online Library

Steatosis in the Liver

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Abstract

Accumulation of triacylglycerols within the cytoplasm of hepatocytes to the degree that lipid droplets are visible microscopically is called liver steatosis. Most commonly, it occurs when there is an imbalance between the delivery or synthesis of fatty acids in the liver and their disposal through oxidative pathways or secretion into the blood as a component of triacylglycerols in very low density lipoprotein. This disorder is called nonalcoholic fatty liver disease (NAFLD) in the absence of alcoholic abuse and viral hepatitis, and it is often associated with insulin resistance, obesity and type 2 diabetes. Also, liver steatosis can be induced by many other causes including excessive alcohol consumption, infection with genotype 3 hepatitis C virus and certain medications. Whereas hepatic triacylglycerol accumulation was once considered the ultimate effector of hepatic lipotoxicity, triacylglycerols per se are quite inert and do not induce insulin resistance or cellular injury. Rather, lipotoxic injury in the liver appears to be mediated by the global ongoing fatty acid enrichment in the liver, paralleling the development of insulin resistance. A considerable number of fatty acid metabolites may be responsible for hepatic lipotoxicity and liver injury. Additional key contributors include hepatic cytosolic lipases and the “lipophagy” of lipid droplets, as sources of hepatic fatty acids. The specific origin of the lipids, mainly triacylglycerols, accumulating in liver has been unraveled by recent kinetic studies, and identifying the origin of the accumulated triacylglycerols in the liver of patients with NAFLD may direct the prevention and treatment of this condition. © 2013 American Physiological Society. Compr Physiol 3:1493‐1532, 2013.

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Figure 1. Figure 1. (A) Fatty acid carbon atoms are numbered often starting at the carboxyl end. (B) The position of a double bond can be denoted by counting from the distal end, with the ω carbon atom (the methyl carbon) as number 1 (green). (C) The carboxylic acid group (red) is shown in its ionized form. (D) The International Union of Pure and Applied Chemists (IUPAC) Δ and common ω numbering systems.
Figure 2. Figure 2. Molecular structures of (A) saturated, (B) monounsaturated, (C) trans fatty, and (D) polyunsaturated fatty acids. The standard chemical formulae (left panel), the perspective formulae (middle panel), and the space‐filling models (right panel) of various fatty acids are shown. Both (B) oleic acid (cis 18:1ω9) and (C) elaidic acid (trans 18:1ω9) are 18‐carbon fatty acids with a single double bond. However, oleic acid has a cis double bond (hydrogen atoms are on the same side of the bond), whereas elaidic acid has a trans double bond (hydrogen atoms are on opposite sides of the bond). Of note, in a cis monounsaturated fatty acid (oleic acid), the double bond induces a degree of structural rigidity and creates a kink in the chain while the rest of the chain is free to rotate about the other C–C bonds. In a trans monounsaturated fatty acid (elaidic acid), a more linear rigid structure is created and this diminishes membrane fluidity when incorporated into membrane lipids. The trans bond imparts a structure more similar to that of saturated fats, altering the physiological properties and effects of the fatty acid.
Figure 3. Figure 3. (A) Triacylglycerols are triesters of glycerol, and each of the three hydroxyl (–OH) groups of glycerol forms an ester group by reaction with the carboxyl (–COOH) group of a fatty acid to form the triacylglycerol molecule. R1, R2, and R3 are fatty acids located at stereospecific numbers (sn)‐1, ‐2 and ‐3, respectively. (B) Diacylglycerols and (C) monoacylglycerols contain two and one fatty acids, respectively. R = hydrocarbon chain.
Figure 4. Figure 4. The general features of lipid balance across the body. There are three sources for lipids entering the small intestine for intestinal absorption: (i) dietary lipids; (ii) biliary lipids; and (iii) desquamated epithelial cells of the gastrointestinal tract. Likewise, there are two major pathways for the excretion of lipid from the body: the excretion of lipids from the body through (i) the gastrointestinal tract and (ii) skin. Because total input of lipids into the body must equal total output in the steady state, the body pool of lipids is kept constant. As a result, normal metabolic homeostasis prevents a potential accumulation of fat and cholesterol in the body. Of note is that in children, there is necessarily a greater input of fat and cholesterol into the body than output since there is a net accumulation of fat and cholesterol allowing for body weight gain with growth.
Figure 5. Figure 5. Putative pathways for uptake of fatty acids by the enterocytes based on the current understanding of fatty acid transport across the apical membranes of enterocytes. Because of their less hydrophobic nature, (A) short‐chain fatty acids may traverse the apical membrane by simple passive diffusion and may be absorbed into the mesenteric venous blood and then the portal vein. (B) Long‐chain fatty acids can be transported by fatty acid transport protein 4 (FATP4). (C) Alternatively, CD36 (also referred to as fatty acid translocase; 88 kDa), alone or together with the peripheral membrane protein plasma membrane‐associated fatty acid‐binding protein (FABPpm; 43 kDa) accepts fatty acids at the cell surface to increase their local concentrations. This could help CD36 actively transport fatty acids across the apical membrane of the enterocyte. Once at the inner side of the membrane, fatty acids are bound by cytoplasmic FABP (FABPc) before entering metabolic pathways. Some fatty acids may be transported by fatty acid transport proteins and rapidly thioesterified by plasma membrane acyl‐CoA synthetase 1 (ACS1) to form acyl‐CoA esters. Acyl‐CoA is used for triacylglycerol synthesis in the enterocyte, which is then a substrate for chylomicron formation and secretion into the lymph.
Figure 6. Figure 6. Elongation and unsaturation of fatty acids from a saturated fatty acid palmitic acid (16:0) in the liver. De novo lipogenesis from glucose as a substrate generates saturated fatty acids such as palmitic acid. Palmitic acid is further elongated and desaturated to form the abundant monounsaturated fatty acids such as oleic acid (18:1ω9). Oleic acid is incorporated into triacylglycerol.
Figure 7. Figure 7. Pathway of fatty acid elongation in mitochondria. In humans, the preferred elongation substrate is palmitoyl‐CoA, which is converted exclusively to stearic acid (18:0) in most tissues including the liver.
Figure 8. Figure 8. Positions in the fatty acid chain where desaturation can occur in humans. The human fatty acid desaturase systems can desaturate various chain lengths at Δ4, Δ5, Δ6, and Δ9 positions. However, humans cannot introduce double bonds beyond carbons 9 and 10 and must have the polyunsaturated fatty acids linoleic (18:2 cis‐Δ9,12), linolenic (18:3 cis‐Δ9,12,15), and arachidonic (20:4 cis‐Δ5,8,11,14) acids provided in the diet. These fatty acids are thus essential fatty acids in humans.
Figure 9. Figure 9. Transfer of a fatty acid from the adipose tissues to the liver and into the mitochondrial matrix for β‐oxidation. The rate of fatty acid release from the adipose tissues affects the total amount of fatty acid available as a fuel for the liver. Abbreviation: ATGL, adipose triglyceride lipase; FAD, flavin adenine dinucleotide; FADH2, the reduced form of FAD; HSL, hormone‐sensitive lipase; NAD+, nicotinamide adenine dinucleotide; NADH, the reduced form of NAD+. See text for details.
Figure 10. Figure 10. Pathways of triacylglycerol biosynthesis in the liver. Both glucose and fructose generate triose phosphate intermediates that form the glycerol backbone of triacylglycerol. R = hydrocarbon chain.
Figure 11. Figure 11. The regulation of fatty acid and triacylglycerol biosynthesis by sterol regulatory element‐binding protein‐1c (SREBP‐1c). In the liver, SREBP‐1c preferentially activates the genes involved fatty acid and triacylglycerol metabolism.
Figure 12. Figure 12. This diagram shows fatty acid balance across the liver, indicating three major (solid lines) and two minor (dashed lines) sources of fatty acids entering the hepatocyte (blue lines) and three main pathways for their utilization (brown lines) for triacylglycerol synthesis, oxidation, and phospholipid synthesis in the hepatocyte. Dietary fatty acids go to the liver due to “spillover” of fatty acids released by lipoprotein lipase and hepatic lipase mediated lipolysis of lipoprotein triacylglycerols in capillaries of adipose tissues and other tissues. Triacylglycerols are packaged with other lipids and apolipoproteins to produce very‐low‐density lipoproteins (VLDL). Triacylglycerols accumulate in the liver when their synthesis exceeds VLDL formation and export, thus leading to hepatic steatosis. See text for details.
Figure 13. Figure 13. Very‐low‐density lipoprotein (VLDL) metabolism. The cycle begins with the hepatic synthesis of nascent VLDL particles. These particles contain apolipoproteins (apo)B‐100 and apoE. Hepatic VLDL assembly involves the lipidation of a newly synthesized apoB‐100 molecule with triacylglycerols (TG). This step is achieved through the action of microsomal triglyceride transfer protein. A further step is the formation of mature VLDL particles, which are enriched with cholesteryl esters and possibly other apolipoproteins, some of which are derived from HDL catabolism. After secretion into the circulation, contact of mature VLDL with the lipolytic action of lipoprotein lipase (apoC‐II acting as primary ligand) results the partial delipidation of VLDL into VLDL remnants which are smaller and enriched in apoB‐100 and apoE. The resulting fatty acids are mostly taken up locally at the site of release from VLDL. The destiny of the VLDL remnants is to be cleared in the liver (LDL and remnant receptors) or to undergo delipidation by hepatic triglyceride lipase to yield LDL particles containing apoB‐100.
Figure 14. Figure 14. Multiple biologically active lipid metabolites are generated during the metabolism of fatty acids and production of triacylglycerols. Many of these have been implicated in causing lipotoxicity manifested as endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, inflammation, and necrosis. Abbreviations: ACSL, acyl‐CoA synthase; AGPAT, acyl‐glycerolphosphate acyltransferase; ATGL, adipose triglyceride lipase; CPT, choline phosphotransferase; DAG, diacylglycerol; DAGK, diacylglycerol kinase; DGATs, diacylglycerol acyltransferases; FA, fatty acids; GPAT, glycerol monophosphate acyltransferase; HSL, hormone‐sensitive lipase; LPA, lysophosphatidic acid; LPAAT, lysophosphatidic acid acyltransferase; LPAP, lysophosphatidic acid phosphatase; LPC, lysophosphatidylcholine; LysoPLD, lysophospholipase D; MAG, monoacylglycerol; MAGK, monoacylglycerol kinase; MGL, monoacylglycerol lipase; MOGAT, monoacylglycerol acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PLA2, phospholipase A2; PLD, phospholipase D; TG, triacylglycerols.
Figure 15. Figure 15. Lipid droplets are enclosed by a monolayer of phospholipid and droplet‐associated proteins which stabilize them within the cytoplasm of adipocytes (left panel) and hepatocytes (right panel). In obese humans, reduced expression of cell death‐inducing DNA fragmentation factor 45‐like effector proteins (CIDEs) and perilipin 1 (PLIN1) allows increased amounts of fatty acids to be released by lipolysis. These fatty acids act locally and enter the bloodstream, where they activate inflammatory pathways, promote ectopic lipid deposition in peripheral tissues, and impair insulin signaling. Fatty acids from adipocyte lipolysis or the diet lead to a large amount of neutral lipid accumulation in lipid droplets in hepatocytes and incorporation of CIDE, PLIN, adipose triglyceride lipase (ATGL) and patatin‐like phospholipase containing 3 (PNPLA3) on the surface of lipid droplets. In the liver, increased fatty acid accumulation and lipid droplet formation are often associated with increased diacylglycerol and inflammatory cytokine production. Diacylglycerol stimulates atypical protein kinase C (PKC), and fatty acids and cytokines activate inflammatory signaling pathways. These alterations can impair insulin signaling and thus contribute to insulin resistance. In hepatocytes, insulin resistance is marked by increased hepatic gluconeogenesis and reduced glycogen formation. Notably, mutations in the phospholipase PNPLA3 result in hepatic steatosis.
Figure 16. Figure 16. The proposed models of the cell death‐inducing DNA fragmentation factor 45‐like effector protein (CIDE)‐mediated lipid transfer and lipid droplet growth. (A) CIDE proteins localized in lipid droplets protects against lipolysis by adipose triglyceride lipase (ATGL) or hormone‐sensitive lipase (HSL) and promotes triacylglycerol accumulation. (B) When clustered and enriched at the lipid droplet contacting site, CIDE proteins may provide a tethering force for stable lipid droplet attachment and recruit other proteins to form a complex at the lipid droplet contacting site. CIDE‐initiated protein complex may deform phospholipid monolayer to generate a pore (or channel‐like) structure at the lipid droplet contacting site, resulting in neutral lipid exchange among contacted lipid droplets and net triacylglycerol transfer from smaller to larger lipid droplets due to the internal pressure difference. The inset indicates an enlarged portion of the lipid droplet contacting site at where CIDE proteins are focally enriched and shows a directional net lipid transfer from a small to a large lipid droplet by a white arrow, thus leading to lipid droplet growth.
Figure 17. Figure 17. The proposed models promote the development of steatosis in the liver by a signaling pathway regulated by the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and the cell death‐inducing DNA fragmentation factor 45‐like effector protein (CIDE). After being activated by PPARγ in the nucleus of the heaptocyte, (A) CIDE proteins promote lipid droplet clustering, (B) protect against lipolysis by lipases such as adipose triglyceride lipase (ATGL) or hormone‐sensitive lipase (HSL), and (C) inhibit mitochondrial β‐oxidation. AMP‐activated protein kinase (AMPK) may be involved in this inhibitory action of CIDE proteins. (D) In addition, CIDE proteins may mediate VLDL lipidation in the endoplasmic reticulum and Golgi through the direct delivery of triacylglycerol from cytosolic lipid droplets to pre‐VLDL particles that are attached to the membrane of the endoplasmic reticulum and Golgi. When triacylglycerol‐rich VLDL secretion cannot remove lipids from the liver, lipid droplet formation allows excess lipid accumulation in the liver in a relatively benign form, thus leading to hepatic steatosis and preventing lipotoxic injury and apoptosis induced by other fatty acid metabolites.
Figure 18. Figure 18. In the context of insulin resistance, excessive fatty acid (FA) flow through the liver following lipolysis in the adipose tissues and also lipophagy and hepatic de novo lipogenesis (DNL) following a carbohydrate‐enriched diet (fructose is especially implicated). Fatty acids are also derived from lipoprotein remnants and from chylomicrons resulting from intestinal fat absorption followed by spillover into the circulation during intravascular lipolysis. The hepatic pool of fatty acids is therefore obtained via DNL, influx following lipolysis and lysosomal breakdown of triacylglycerol‐rich lipoprotein remnants. The fate of fatty acids is normally to undergo oxidation mainly in mitochondria, and partially in peroxisomes and the smooth endoplasmic reticulum (ER). Formation of reactive oxygen species (ROS), that is, hydrogen peroxide and superoxide, and oxidant stress following oxidation is normally counteracted by specific antioxidant buffering systems (e.g., glutathione). Fatty acids undergo esterification with glycerol to form triacylglycerols (TG), which represents a lipid storage system in the liver, eventually leading to lipid droplets and steatosis. Alternatively, triacylglycerols can be exported into VLDL particles. Cytosolic lipases such as adipose triglyceride lipase can transfer additional fatty acids from lipid droplets to the fatty acid pool. Lipid droplet breakdown also occurs by autophagy (lipophagy), a process in which lipid droplets are sequestered in autophagosomes that fuse with lysosomes resulting in the breakdown of lipid droplet components by lysosomal enzymes. This pathway is regulated by changes in gene expression and increases when the cell is stressed either by nutrient deprivation or an excess of lipids. Increased autophagy generates more fatty acids, which contribute to the fatty acid pool. The lipotoxicity model of liver injury suggests that fatty acids are transformed into active metabolites able to orchestrate the hepatocellular damage, that is, ER stress, inflammation, necrosis, apoptosis, cellular ballooning, and formation of Mallory‐Denk bodies that characterize NASH.


Figure 1. (A) Fatty acid carbon atoms are numbered often starting at the carboxyl end. (B) The position of a double bond can be denoted by counting from the distal end, with the ω carbon atom (the methyl carbon) as number 1 (green). (C) The carboxylic acid group (red) is shown in its ionized form. (D) The International Union of Pure and Applied Chemists (IUPAC) Δ and common ω numbering systems.


Figure 2. Molecular structures of (A) saturated, (B) monounsaturated, (C) trans fatty, and (D) polyunsaturated fatty acids. The standard chemical formulae (left panel), the perspective formulae (middle panel), and the space‐filling models (right panel) of various fatty acids are shown. Both (B) oleic acid (cis 18:1ω9) and (C) elaidic acid (trans 18:1ω9) are 18‐carbon fatty acids with a single double bond. However, oleic acid has a cis double bond (hydrogen atoms are on the same side of the bond), whereas elaidic acid has a trans double bond (hydrogen atoms are on opposite sides of the bond). Of note, in a cis monounsaturated fatty acid (oleic acid), the double bond induces a degree of structural rigidity and creates a kink in the chain while the rest of the chain is free to rotate about the other C–C bonds. In a trans monounsaturated fatty acid (elaidic acid), a more linear rigid structure is created and this diminishes membrane fluidity when incorporated into membrane lipids. The trans bond imparts a structure more similar to that of saturated fats, altering the physiological properties and effects of the fatty acid.


Figure 3. (A) Triacylglycerols are triesters of glycerol, and each of the three hydroxyl (–OH) groups of glycerol forms an ester group by reaction with the carboxyl (–COOH) group of a fatty acid to form the triacylglycerol molecule. R1, R2, and R3 are fatty acids located at stereospecific numbers (sn)‐1, ‐2 and ‐3, respectively. (B) Diacylglycerols and (C) monoacylglycerols contain two and one fatty acids, respectively. R = hydrocarbon chain.


Figure 4. The general features of lipid balance across the body. There are three sources for lipids entering the small intestine for intestinal absorption: (i) dietary lipids; (ii) biliary lipids; and (iii) desquamated epithelial cells of the gastrointestinal tract. Likewise, there are two major pathways for the excretion of lipid from the body: the excretion of lipids from the body through (i) the gastrointestinal tract and (ii) skin. Because total input of lipids into the body must equal total output in the steady state, the body pool of lipids is kept constant. As a result, normal metabolic homeostasis prevents a potential accumulation of fat and cholesterol in the body. Of note is that in children, there is necessarily a greater input of fat and cholesterol into the body than output since there is a net accumulation of fat and cholesterol allowing for body weight gain with growth.


Figure 5. Putative pathways for uptake of fatty acids by the enterocytes based on the current understanding of fatty acid transport across the apical membranes of enterocytes. Because of their less hydrophobic nature, (A) short‐chain fatty acids may traverse the apical membrane by simple passive diffusion and may be absorbed into the mesenteric venous blood and then the portal vein. (B) Long‐chain fatty acids can be transported by fatty acid transport protein 4 (FATP4). (C) Alternatively, CD36 (also referred to as fatty acid translocase; 88 kDa), alone or together with the peripheral membrane protein plasma membrane‐associated fatty acid‐binding protein (FABPpm; 43 kDa) accepts fatty acids at the cell surface to increase their local concentrations. This could help CD36 actively transport fatty acids across the apical membrane of the enterocyte. Once at the inner side of the membrane, fatty acids are bound by cytoplasmic FABP (FABPc) before entering metabolic pathways. Some fatty acids may be transported by fatty acid transport proteins and rapidly thioesterified by plasma membrane acyl‐CoA synthetase 1 (ACS1) to form acyl‐CoA esters. Acyl‐CoA is used for triacylglycerol synthesis in the enterocyte, which is then a substrate for chylomicron formation and secretion into the lymph.


Figure 6. Elongation and unsaturation of fatty acids from a saturated fatty acid palmitic acid (16:0) in the liver. De novo lipogenesis from glucose as a substrate generates saturated fatty acids such as palmitic acid. Palmitic acid is further elongated and desaturated to form the abundant monounsaturated fatty acids such as oleic acid (18:1ω9). Oleic acid is incorporated into triacylglycerol.


Figure 7. Pathway of fatty acid elongation in mitochondria. In humans, the preferred elongation substrate is palmitoyl‐CoA, which is converted exclusively to stearic acid (18:0) in most tissues including the liver.


Figure 8. Positions in the fatty acid chain where desaturation can occur in humans. The human fatty acid desaturase systems can desaturate various chain lengths at Δ4, Δ5, Δ6, and Δ9 positions. However, humans cannot introduce double bonds beyond carbons 9 and 10 and must have the polyunsaturated fatty acids linoleic (18:2 cis‐Δ9,12), linolenic (18:3 cis‐Δ9,12,15), and arachidonic (20:4 cis‐Δ5,8,11,14) acids provided in the diet. These fatty acids are thus essential fatty acids in humans.


Figure 9. Transfer of a fatty acid from the adipose tissues to the liver and into the mitochondrial matrix for β‐oxidation. The rate of fatty acid release from the adipose tissues affects the total amount of fatty acid available as a fuel for the liver. Abbreviation: ATGL, adipose triglyceride lipase; FAD, flavin adenine dinucleotide; FADH2, the reduced form of FAD; HSL, hormone‐sensitive lipase; NAD+, nicotinamide adenine dinucleotide; NADH, the reduced form of NAD+. See text for details.


Figure 10. Pathways of triacylglycerol biosynthesis in the liver. Both glucose and fructose generate triose phosphate intermediates that form the glycerol backbone of triacylglycerol. R = hydrocarbon chain.


Figure 11. The regulation of fatty acid and triacylglycerol biosynthesis by sterol regulatory element‐binding protein‐1c (SREBP‐1c). In the liver, SREBP‐1c preferentially activates the genes involved fatty acid and triacylglycerol metabolism.


Figure 12. This diagram shows fatty acid balance across the liver, indicating three major (solid lines) and two minor (dashed lines) sources of fatty acids entering the hepatocyte (blue lines) and three main pathways for their utilization (brown lines) for triacylglycerol synthesis, oxidation, and phospholipid synthesis in the hepatocyte. Dietary fatty acids go to the liver due to “spillover” of fatty acids released by lipoprotein lipase and hepatic lipase mediated lipolysis of lipoprotein triacylglycerols in capillaries of adipose tissues and other tissues. Triacylglycerols are packaged with other lipids and apolipoproteins to produce very‐low‐density lipoproteins (VLDL). Triacylglycerols accumulate in the liver when their synthesis exceeds VLDL formation and export, thus leading to hepatic steatosis. See text for details.


Figure 13. Very‐low‐density lipoprotein (VLDL) metabolism. The cycle begins with the hepatic synthesis of nascent VLDL particles. These particles contain apolipoproteins (apo)B‐100 and apoE. Hepatic VLDL assembly involves the lipidation of a newly synthesized apoB‐100 molecule with triacylglycerols (TG). This step is achieved through the action of microsomal triglyceride transfer protein. A further step is the formation of mature VLDL particles, which are enriched with cholesteryl esters and possibly other apolipoproteins, some of which are derived from HDL catabolism. After secretion into the circulation, contact of mature VLDL with the lipolytic action of lipoprotein lipase (apoC‐II acting as primary ligand) results the partial delipidation of VLDL into VLDL remnants which are smaller and enriched in apoB‐100 and apoE. The resulting fatty acids are mostly taken up locally at the site of release from VLDL. The destiny of the VLDL remnants is to be cleared in the liver (LDL and remnant receptors) or to undergo delipidation by hepatic triglyceride lipase to yield LDL particles containing apoB‐100.


Figure 14. Multiple biologically active lipid metabolites are generated during the metabolism of fatty acids and production of triacylglycerols. Many of these have been implicated in causing lipotoxicity manifested as endoplasmic reticulum stress, mitochondrial dysfunction, apoptosis, inflammation, and necrosis. Abbreviations: ACSL, acyl‐CoA synthase; AGPAT, acyl‐glycerolphosphate acyltransferase; ATGL, adipose triglyceride lipase; CPT, choline phosphotransferase; DAG, diacylglycerol; DAGK, diacylglycerol kinase; DGATs, diacylglycerol acyltransferases; FA, fatty acids; GPAT, glycerol monophosphate acyltransferase; HSL, hormone‐sensitive lipase; LPA, lysophosphatidic acid; LPAAT, lysophosphatidic acid acyltransferase; LPAP, lysophosphatidic acid phosphatase; LPC, lysophosphatidylcholine; LysoPLD, lysophospholipase D; MAG, monoacylglycerol; MAGK, monoacylglycerol kinase; MGL, monoacylglycerol lipase; MOGAT, monoacylglycerol acyltransferase; PA, phosphatidic acid; PAP, phosphatidic acid phosphatase; PC, phosphatidylcholine; PLA2, phospholipase A2; PLD, phospholipase D; TG, triacylglycerols.


Figure 15. Lipid droplets are enclosed by a monolayer of phospholipid and droplet‐associated proteins which stabilize them within the cytoplasm of adipocytes (left panel) and hepatocytes (right panel). In obese humans, reduced expression of cell death‐inducing DNA fragmentation factor 45‐like effector proteins (CIDEs) and perilipin 1 (PLIN1) allows increased amounts of fatty acids to be released by lipolysis. These fatty acids act locally and enter the bloodstream, where they activate inflammatory pathways, promote ectopic lipid deposition in peripheral tissues, and impair insulin signaling. Fatty acids from adipocyte lipolysis or the diet lead to a large amount of neutral lipid accumulation in lipid droplets in hepatocytes and incorporation of CIDE, PLIN, adipose triglyceride lipase (ATGL) and patatin‐like phospholipase containing 3 (PNPLA3) on the surface of lipid droplets. In the liver, increased fatty acid accumulation and lipid droplet formation are often associated with increased diacylglycerol and inflammatory cytokine production. Diacylglycerol stimulates atypical protein kinase C (PKC), and fatty acids and cytokines activate inflammatory signaling pathways. These alterations can impair insulin signaling and thus contribute to insulin resistance. In hepatocytes, insulin resistance is marked by increased hepatic gluconeogenesis and reduced glycogen formation. Notably, mutations in the phospholipase PNPLA3 result in hepatic steatosis.


Figure 16. The proposed models of the cell death‐inducing DNA fragmentation factor 45‐like effector protein (CIDE)‐mediated lipid transfer and lipid droplet growth. (A) CIDE proteins localized in lipid droplets protects against lipolysis by adipose triglyceride lipase (ATGL) or hormone‐sensitive lipase (HSL) and promotes triacylglycerol accumulation. (B) When clustered and enriched at the lipid droplet contacting site, CIDE proteins may provide a tethering force for stable lipid droplet attachment and recruit other proteins to form a complex at the lipid droplet contacting site. CIDE‐initiated protein complex may deform phospholipid monolayer to generate a pore (or channel‐like) structure at the lipid droplet contacting site, resulting in neutral lipid exchange among contacted lipid droplets and net triacylglycerol transfer from smaller to larger lipid droplets due to the internal pressure difference. The inset indicates an enlarged portion of the lipid droplet contacting site at where CIDE proteins are focally enriched and shows a directional net lipid transfer from a small to a large lipid droplet by a white arrow, thus leading to lipid droplet growth.


Figure 17. The proposed models promote the development of steatosis in the liver by a signaling pathway regulated by the nuclear receptor peroxisome proliferator‐activated receptor γ (PPARγ) and the cell death‐inducing DNA fragmentation factor 45‐like effector protein (CIDE). After being activated by PPARγ in the nucleus of the heaptocyte, (A) CIDE proteins promote lipid droplet clustering, (B) protect against lipolysis by lipases such as adipose triglyceride lipase (ATGL) or hormone‐sensitive lipase (HSL), and (C) inhibit mitochondrial β‐oxidation. AMP‐activated protein kinase (AMPK) may be involved in this inhibitory action of CIDE proteins. (D) In addition, CIDE proteins may mediate VLDL lipidation in the endoplasmic reticulum and Golgi through the direct delivery of triacylglycerol from cytosolic lipid droplets to pre‐VLDL particles that are attached to the membrane of the endoplasmic reticulum and Golgi. When triacylglycerol‐rich VLDL secretion cannot remove lipids from the liver, lipid droplet formation allows excess lipid accumulation in the liver in a relatively benign form, thus leading to hepatic steatosis and preventing lipotoxic injury and apoptosis induced by other fatty acid metabolites.


Figure 18. In the context of insulin resistance, excessive fatty acid (FA) flow through the liver following lipolysis in the adipose tissues and also lipophagy and hepatic de novo lipogenesis (DNL) following a carbohydrate‐enriched diet (fructose is especially implicated). Fatty acids are also derived from lipoprotein remnants and from chylomicrons resulting from intestinal fat absorption followed by spillover into the circulation during intravascular lipolysis. The hepatic pool of fatty acids is therefore obtained via DNL, influx following lipolysis and lysosomal breakdown of triacylglycerol‐rich lipoprotein remnants. The fate of fatty acids is normally to undergo oxidation mainly in mitochondria, and partially in peroxisomes and the smooth endoplasmic reticulum (ER). Formation of reactive oxygen species (ROS), that is, hydrogen peroxide and superoxide, and oxidant stress following oxidation is normally counteracted by specific antioxidant buffering systems (e.g., glutathione). Fatty acids undergo esterification with glycerol to form triacylglycerols (TG), which represents a lipid storage system in the liver, eventually leading to lipid droplets and steatosis. Alternatively, triacylglycerols can be exported into VLDL particles. Cytosolic lipases such as adipose triglyceride lipase can transfer additional fatty acids from lipid droplets to the fatty acid pool. Lipid droplet breakdown also occurs by autophagy (lipophagy), a process in which lipid droplets are sequestered in autophagosomes that fuse with lysosomes resulting in the breakdown of lipid droplet components by lysosomal enzymes. This pathway is regulated by changes in gene expression and increases when the cell is stressed either by nutrient deprivation or an excess of lipids. Increased autophagy generates more fatty acids, which contribute to the fatty acid pool. The lipotoxicity model of liver injury suggests that fatty acids are transformed into active metabolites able to orchestrate the hepatocellular damage, that is, ER stress, inflammation, necrosis, apoptosis, cellular ballooning, and formation of Mallory‐Denk bodies that characterize NASH.
References
 1.Abumrad N, Harmon C, Ibrahimi A. Membrane transport of long‐chain fatty acids: Evidence for a facilitated process. J Lipid Res 39: 2309‐2318, 1998.
 2.Abumrad NA, Davidson NO. Role of the gut in lipid homeostasis. Physiol Rev 92: 1061‐1085, 2012.
 3.Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro‐Paavonen A, Westerbacka J, Vehkavaara S, Hakkinen A, Olofsson SO, Yki‐Jarvinen H, Boren J. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia 49: 755‐765, 2006.
 4.Alkhouri N, Dixon LJ, Feldstein AE. Lipotoxicity in nonalcoholic fatty liver disease: Not all lipids are created equal. Expert Rev Gastroenterol Hepatol 3: 445‐451, 2009.
 5.Alwayn IP, Andersson C, Zauscher B, Gura K, Nose V, Puder M. Omega‐3 fatty acids improve hepatic steatosis in a murine model: Potential implications for the marginal steatotic liver donor. Transplantation 79: 606‐608, 2005.
 6.Alwayn IP, Gura K, Nose V, Zausche B, Javid P, Garza J, Verbesey J, Voss S, Ollero M, Andersson C, Bistrian B, Folkman J, Puder M. Omega‐3 fatty acid supplementation prevents hepatic steatosis in a murine model of nonalcoholic fatty liver disease. Pediatric Res 57: 445‐452, 2005.
 7.Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 346: 1221‐1231, 2002.
 8.Augoustides‐Savvopoulou P, Luka Z, Karyda S, Stabler SP, Allen RH, Patsiaoura K, Wagner C, Mudd SH. Glycine N ‐methyltransferase deficiency: A new patient with a novel mutation. J Inherit Metab Dis 26: 745‐759, 2003.
 9.Azzout‐Marniche D, Becard D, Guichard C, Foretz M, Ferre P, Foufelle F. Insulin effects on sterol regulatory‐element‐binding protein‐1c (SREBP‐1c) transcriptional activity in rat hepatocytes. Biochem J 350(Pt 2): 389‐393, 2000.
 10.Bacon BR, Farahvash MJ, Janney CG, Neuschwander‐Tetri BA. Nonalcoholic steatohepatitis: An expanded clinical entity. Gastroenterology 107: 1103‐1109, 1994.
 11.Bardot O, Aldridge TC, Latruffe N, Green S. PPAR‐RXR heterodimer activates a peroxisome proliferator response element upstream of the bifunctional enzyme gene. Biochem Biophys Res Commun 192: 37‐45, 1993.
 12.Barish GD, Narkar VA, Evans RM. PPAR delta: A dagger in the heart of the metabolic syndrome. J Clin Invest 116: 590‐597, 2006.
 13.Bavner A, Sanyal S, Gustafsson JA, Treuter E. Transcriptional corepression by SHP: Molecular mechanisms and physiological consequences. Trends Endocrinol Metab 16: 478‐488, 2005.
 14.Bertilsson G, Heidrich J, Svensson K, Asman M, Jendeberg L, Sydow‐Backman M, Ohlsson R, Postlind H, Blomquist P, Berkenstam A. Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction. Proc Natl Acad Sci U S A 95: 12208‐12213, 1998.
 15.Blanchette‐Mackie EJ, Dwyer NK, Barber T, Coxey RA, Takeda T, Rondinone CM, Theodorakis JL, Greenberg AS, Londos C. Perilipin is located on the surface layer of intracellular lipid droplets in adipocytes. J Lipid Res 36: 1211‐1226, 1995.
 16.Blumberg B, Sabbagh W, Jr., Juguilon H, Bolado J, Jr., van Meter CM, Ong ES, Evans RM. SXR, a novel steroid and xenobiotic‐sensing nuclear receptor. Genes Dev 12: 3195‐3205, 1998.
 17.Bonen A, Chabowski A, Luiken JJ, Glatz JF. Is membrane transport of FFA mediated by lipid, protein, or both? Mechanisms and regulation of protein‐mediated cellular fatty acid uptake: Molecular, biochemical, and physiological evidence. Physiology (Bethesda) 22: 15‐29, 2007.
 18.Bostrom P, Andersson L, Li L, Perkins R, Hojlund K, Boren J, Olofsson SO. The assembly of lipid droplets and its relation to cellular insulin sensitivity. Biochem Soc Trans 37: 981‐985, 2009.
 19.Boulias K, Katrakili N, Bamberg K, Underhill P, Greenfield A, Talianidis I. Regulation of hepatic metabolic pathways by the orphan nuclear receptor SHP. EMBO J 24: 2624‐2633, 2005.
 20.Brasaemle DL. Thematic review series: Adipocyte biology. The perilipin family of structural lipid droplet proteins: Stabilization of lipid droplets and control of lipolysis. J Lipid Res 48: 2547‐2559, 2007.
 21.Brasaemle DL, Rubin B, Harten IA, Gruia‐Gray J, Kimmel AR, Londos C. Perilipin A increases triacylglycerol storage by decreasing the rate of triacylglycerol hydrolysis. J Biol Chem 275: 38486‐38493, 2000.
 22.Brown MS, Goldstein JL. The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane‐bound transcription factor. Cell 89: 331‐340, 1997.
 23.Browning JD, Horton JD. Molecular mediators of hepatic steatosis and liver injury. J Clin Invest 114: 147‐152, 2004.
 24.Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: Impact of ethnicity. Hepatology 40: 1387‐1395, 2004.
 25.Brunt EM. Nonalcoholic steatohepatitis: Definition and pathology. Semin Liver Dis 21: 3‐16, 2001.
 26.Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander‐Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: A proposal for grading and staging the histological lesions. Am J Gastroenterol 94: 2467‐2474, 1999.
 27.Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander‐Tetri BA. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: Distinct clinicopathologic meanings. Hepatology 53: 810‐820, 2011.
 28.Brunt EM, Neuschwander‐Tetri BA, Oliver D, Wehmeier KR, Bacon BR. Nonalcoholic steatohepatitis: Histologic features and clinical correlations with 30 blinded biopsy specimens. Hum Pathol 35: 1070‐1082, 2004.
 29.Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, Rizzetto M. Insulin resistance in non‐diabetic patients with non‐alcoholic fatty liver disease: Sites and mechanisms. Diabetologia 48: 634‐642, 2005.
 30.Byrne CD, Olufadi R, Bruce KD, Cagampang FR, Ahmed MH. Metabolic disturbances in non‐alcoholic fatty liver disease. Clin Sci (Lond) 116: 539‐564, 2009.
 31.Caldwell SH, Patrie JT, Brunt EM, Redick JA, Davis CA, Park SH, Neuschwander‐Tetri BA. The effects of 48 weeks of rosiglitazone on hepatocyte mitochondria in human nonalcoholic steatohepatitis. Hepatology 46: 1101‐1107, 2007.
 32.Capanni M, Calella F, Biagini MR, Genise S, Raimondi L, Bedogni G, Svegliati‐Baroni G, Sofi F, Milani S, Abbate R, Surrenti C, Casini A. Prolonged n‐3 polyunsaturated fatty acid supplementation ameliorates hepatic steatosis in patients with non‐alcoholic fatty liver disease: A pilot study. Aliment Pharmacol Ther 23: 1143‐1151, 2006.
 33.Cariou B. The farnesoid X receptor (FXR) as a new target in non‐alcoholic steatohepatitis. Diabetes Metab 34: 685‐691, 2008.
 34.Cariou B, van Harmelen K, Duran‐Sandoval D, van Dijk TH, Grefhorst A, Abdelkarim M, Caron S, Torpier G, Fruchart JC, Gonzalez FJ, Kuipers F, Staels B. The farnesoid X receptor modulates adiposity and peripheral insulin sensitivity in mice. J Biol Chem 281: 11039‐11049, 2006.
 35.Cha JY, Repa JJ. The liver X receptor (LXR) and hepatic lipogenesis. The carbohydrate‐response element‐binding protein is a target gene of LXR. J Biol Chem 282: 743‐751, 2007.
 36.Chakravarthy MV, Pan Z, Zhu Y, Tordjman K, Schneider JG, Coleman T, Turk J, Semenkovich CF. “New” hepatic fat activates PPARalpha to maintain glucose, lipid, and cholesterol homeostasis. Cell Metab 1: 309‐322, 2005.
 37.Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non‐alcoholic fatty liver disease: Practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology. Gastroenterology 142: 1592‐1609, 2012.
 38.Chawla A, Lee CH, Barak Y, He W, Rosenfeld J, Liao D, Han J, Kang H, Evans RM. PPARdelta is a very low‐density lipoprotein sensor in macrophages. Proc Natl Acad Sci U S A 100: 1268‐1273, 2003.
 39.Chen G, Liang G, Ou J, Goldstein JL, Brown MS. Central role for liver X receptor in insulin‐mediated activation of Srebp‐1c transcription and stimulation of fatty acid synthesis in liver. Proc Natl Acad Sci U S A 101: 11245‐11250, 2004.
 40.Chen Z, Norris JY, Finck BN. Peroxisome proliferator‐activated receptor‐gamma coactivator‐1alpha (PGC‐1alpha) stimulates VLDL assembly through activation of cell death‐inducing DFFA‐like effector B (CideB). J Biol Chem 285: 25996‐26004, 2010.
 41.Cheung O, Kapoor A, Puri P, Sistrun S, Luketic VA, Sargeant CC, Contos MJ, Shiffman ML, Stravitz RT, Sterling RK, Sanyal AJ. The impact of fat distribution on the severity of nonalcoholic fatty liver disease and metabolic syndrome. Hepatology 46: 1091‐1100, 2007.
 42.Choi SH, Ginsberg HN. Increased very low density lipoprotein (VLDL) secretion, hepatic steatosis, and insulin resistance. Trends Endocrinol Metab 22: 353‐363, 2011.
 43.Choi SS, Diehl AM. Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Curr Opin Lipidol 19: 295‐300, 2008.
 44.Cipriani S, Mencarelli A, Palladino G, Fiorucci S. FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. J Lipid Res 51: 771‐784, 2010.
 45.Clark JM. The epidemiology of nonalcoholic fatty liver disease in adults. J Clin Gastroenterol 40(Suppl 1): S5‐S10, 2006.
 46.Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol 98: 960‐967, 2003.
 47.Claudel T, Inoue Y, Barbier O, Duran‐Sandoval D, Kosykh V, Fruchart J, Fruchart JC, Gonzalez FJ, Staels B. Farnesoid X receptor agonists suppress hepatic apolipoprotein CIII expression. Gastroenterology 125: 544‐555, 2003.
 48.Cole LK, Vance JE, Vance DE. Phosphatidylcholine biosynthesis and lipoprotein metabolism. Biochim Biophys Acta 1821: 754‐761, 2012.
 49.Coleman RA, Lee DP. Enzymes of triacylglycerol synthesis and their regulation. Prog Lipid Res 43: 134‐176, 2004.
 50.Coleman RA, Mashek DG. Mammalian triacylglycerol metabolism: Synthesis, lipolysis, and signaling. Chem Rev 111: 6359‐6386, 2011.
 51.Commerford SR, Peng L, Dube JJ, O'Doherty RM. In vivo regulation of SREBP‐1c in skeletal muscle: Effects of nutritional status, glucose, insulin, and leptin. Am J Physiol Regul Integr Comp Physiol 287: R218‐R227, 2004.
 52.Cortez‐Pinto H, Camilo ME, Baptista A, De Oliveira AG, De Moura MC. Non‐alcoholic fatty liver: Another feature of the metabolic syndrome? Clin Nutr 18: 353‐358, 1999.
 53.Cuchel M, Bloedon LT, Szapary PO, Kolansky DM, Wolfe ML, Sarkis A, Millar JS, Ikewaki K, Siegelman ES, Gregg RE, Rader DJ. Inhibition of microsomal triglyceride transfer protein in familial hypercholesterolemia. N Engl J Med 356: 148‐156, 2007.
 54.Cusi K. Role of insulin resistance and lipotoxicity in non‐alcoholic steatohepatitis. Clin Liver Dis 13: 545‐563, 2009.
 55.Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: Pathophysiology and clinical implications. Gastroenterology 142: 711‐725 e716, 2012.
 56.Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, Girard J, Postic C. Liver‐specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes 55: 2159‐2170, 2006.
 57.Dentin R, Benhamed F, Pegorier JP, Foufelle F, Viollet B, Vaulont S, Girard J, Postic C. Polyunsaturated fatty acids suppress glycolytic and lipogenic genes through the inhibition of ChREBP nuclear protein translocation. J Clin Invest 115: 2843‐2854, 2005.
 58.Dentin R, Girard J, Postic C. Carbohydrate responsive element binding protein (ChREBP) and sterol regulatory element binding protein‐1c (SREBP‐1c): Two key regulators of glucose metabolism and lipid synthesis in liver. Biochimie 87: 81‐86, 2005.
 59.Dentin R, Pegorier JP, Benhamed F, Foufelle F, Ferre P, Fauveau V, Magnuson MA, Girard J, Postic C. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP‐1c on glycolytic and lipogenic gene expression. J Biol Chem 279: 20314‐20326, 2004.
 60.Di Minno MN, Russolillo A, Lupoli R, Ambrosino P, Di Minno A, Tarantino G. Omega‐3 fatty acids for the treatment of non‐alcoholic fatty liver disease. World J Gastroenterol 18: 5839‐5847, 2012.
 61.Ding WX, Li M, Chen X, Ni HM, Lin CW, Gao W, Lu B, Stolz DB, Clemens DL, Yin XM. Autophagy reduces acute ethanol‐induced hepatotoxicity and steatosis in mice. Gastroenterology 139: 1740‐1752, 2010.
 62.Ding WX, Li M, Yin XM. Selective taste of ethanol‐induced autophagy for mitochondria and lipid droplets. Autophagy 7: 248‐249, 2011.
 63.Diogo CV, Grattagliano I, Oliveira PJ, Bonfrate L, Portincasa P. Re‐wiring the circuit: Mitochondria as a pharmacological target in liver disease. Curr Med Chem 18: 5448‐5465, 2011.
 64.Diraison F, Beylot M. Role of human liver lipogenesis and reesterification in triglycerides secretion and in FFA reesterification. Am J Physiol Gastrointest Liver Physiol 274: E321‐E327, 1998.
 65.Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non‐alcoholic fatty liver disease. Diabetes Metab 29: 478‐485, 2003.
 66.Dixon JB, Bhathal PS, O'Brien PE. Nonalcoholic fatty liver disease: Predictors of nonalcoholic steatohepatitis and liver fibrosis in the severely obese. Gastroenterology 121: 91‐100, 2001.
 67.Dong B, Saha PK, Huang W, Chen W, Abu‐Elheiga LA, Wakil SJ, Stevens RD, Ilkayeva O, Newgard CB, Chan L, Moore DD. Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease. Proc Natl Acad Sci U S A 106: 18831‐18836, 2009.
 68.Dong H, Czaja MJ. Regulation of lipid droplets by autophagy. Trends Endocrinol Metab 22: 234‐240, 2011.
 69.Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, Parks EJ. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest 115: 1343‐1351, 2005.
 70.Downes M, Verdecia MA, Roecker AJ, Hughes R, Hogenesch JB, Kast‐Woelbern HR, Bowman ME, Ferrer JL, Anisfeld AM, Edwards PA, Rosenfeld JM, Alvarez JG, Noel JP, Nicolaou KC, Evans RM. A chemical, genetic, and structural analysis of the nuclear bile acid receptor FXR. Mol Cell 11: 1079‐1092, 2003.
 71.Ducharme NA, Bickel PE. Lipid droplets in lipogenesis and lipolysis. Endocrinology 149: 942‐949, 2008.
 72.Ducluzeau PH, Perretti N, Laville M, Andreelli F, Vega N, Riou JP, Vidal H. Regulation by insulin of gene expression in human skeletal muscle and adipose tissue. Evidence for specific defects in type 2 diabetes. Diabetes 50: 1134‐1142, 2001.
 73.Edvardsson U, Ljungberg A, Linden D, William‐Olsson L, Peilot‐Sjogren H, Ahnmark A, Oscarsson J. PPARalpha activation increases triglyceride mass and adipose differentiation‐related protein in hepatocytes. J Lipid Res 47: 329‐340, 2006.
 74.Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, Okunade A, Klein S. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A 106: 15430‐15435, 2009.
 75.Fabbrini E, Mohammed BS, Magkos F, Korenblat KM, Patterson BW, Klein S. Alterations in adipose tissue and hepatic lipid kinetics in obese men and women with nonalcoholic fatty liver disease. Gastroenterology 134: 424‐431, 2008.
 76.Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: Biochemical, metabolic, and clinical implications. Hepatology 51: 679‐689, 2010.
 77.Faergeman NJ, DiRusso CC, Elberger A, Knudsen J, Black PN. Disruption of the Saccharomyces cerevisiae homologue to the murine fatty acid transport protein impairs uptake and growth on long‐chain fatty acids. J Biol Chem 272: 8531‐8538, 1997.
 78.Foretz M, Guichard C, Ferre P, Foufelle F. Sterol regulatory element binding protein‐1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis‐related genes. Proc Natl Acad Sci U S A 96: 12737‐12742, 1999.
 79.Forman BM, Chen J, Evans RM. Hypolipidemic drugs, polyunsaturated fatty acids, and eicosanoids are ligands for peroxisome proliferator‐activated receptors alpha and delta. Proc Natl Acad Sci U S A 94: 4312‐4317, 1997.
 80.Frosig C, Jorgensen SB, Hardie DG, Richter EA, Wojtaszewski JF. 5′‐AMP‐activated protein kinase activity and protein expression are regulated by endurance training in human skeletal muscle. Am J Physiol Endocrinol Metab 286: E411‐E417, 2004.
 81.Fujimoto Y, Itabe H, Sakai J, Makita M, Noda J, Mori M, Higashi Y, Kojima S, Takano T. Identification of major proteins in the lipid droplet‐enriched fraction isolated from the human hepatocyte cell line HuH7. Biochim Biophys Acta 1644: 47‐59, 2004.
 82.Fujita Y, Yamada Y, Kusama M, Yamauchi T, Kamon J, Kadowaki T, Iga T. Sex differences in the pharmacokinetics of pioglitazone in rats. Comp Biochem Physiol C Toxicol Pharmacol 136: 85‐94, 2003.
 83.Gambino R, Cassader M, Pagano G, Durazzo M, Musso G. Polymorphism in microsomal triglyceride transfer protein: A link between liver disease and atherogenic postprandial lipid profile in NASH? Hepatology 45: 1097‐1107, 2007.
 84.Garbarino J, Sturley SL. Saturated with fat: New perspectives on lipotoxicity. Curr Opin Clin Nutr Metab Care 12: 110‐116, 2009.
 85.Gimeno RE, Hirsch DJ, Punreddy S, Sun Y, Ortegon AM, Wu H, Daniels T, Stricker‐Krongrad A, Lodish HF, Stahl A. Targeted deletion of fatty acid transport protein‐4 results in early embryonic lethality. J Biol Chem 278: 49512‐49516, 2003.
 86.Glatz JF, Luiken JJ, Bonen A. Membrane fatty acid transporters as regulators of lipid metabolism: Implications for metabolic disease. Physiol Rev 90: 367‐417, 2010.
 87.Gong J, Sun Z, Li P. CIDE proteins and metabolic disorders. Curr Opin Lipidol 20: 121‐126, 2009.
 88.Gong J, Sun Z, Wu L, Xu W, Schieber N, Xu D, Shui G, Yang H, Parton RG, Li P. Fsp27 promotes lipid droplet growth by lipid exchange and transfer at lipid droplet contact sites. J Cell Biol 195: 953‐963, 2011.
 89.Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA. A regulatory cascade of the nuclear receptors FXR, SHP‐1, and LRH‐1 represses bile acid biosynthesis. Mol Cell 6: 517‐526, 2000.
 90.Grattagliano I, Bonfrate L, Diogo CV, Wang HH, Wang DQ, Portincasa P. Biochemical mechanisms in drug‐induced liver injury: Certainties and doubts. World J Gastroenterol 15: 4865‐4876, 2009.
 91.Grattagliano I, Caraceni P, Calamita G, Ferri D, Gargano I, Palasciano G, Portincasa P. Severe liver steatosis correlates with nitrosative and oxidative stress in rats. Eur J Clin Invest 38: 523‐530, 2008.
 92.Grattagliano I, de Bari O, Bernardo TC, Oliveira PJ, Wang DQ, Portincasa P. Role of mitochondria in nonalcoholic fatty liver disease‐from origin to propagation. Clin Biochem 45: 610‐618, 2012.
 93.Greenberg AS, Coleman RA. Expanding roles for lipid droplets. Trends Endocrinol Metab 22: 195‐196, 2011.
 94.Greenberg AS, Coleman RA, Kraemer FB, McManaman JL, Obin MS, Puri V, Yan QW, Miyoshi H, Mashek DG. The role of lipid droplets in metabolic disease in rodents and humans. J Clin Invest 121: 2102‐2110, 2011.
 95.Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette‐Mackie EJ, Londos C. Perilipin, a major hormonally regulated adipocyte‐specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem 266: 11341‐11346, 1991.
 96.Grefhorst A, Elzinga BM, Voshol PJ, Plosch T, Kok T, Bloks VW, van der Sluijs FH, Havekes LM, Romijn JA, Verkade HJ, Kuipers F. Stimulation of lipogenesis by pharmacological activation of the liver X receptor leads to production of large, triglyceride‐rich very low density lipoprotein particles. J Biol Chem 277: 34182‐34190, 2002.
 97.Gruen ML, Hao M, Piston DW, Hasty AH. Leptin requires canonical migratory signaling pathways for induction of monocyte and macrophage chemotaxis. Am J Physiol Cell Physiol 293: C1481‐C1488, 2007.
 98.Guerrero R, Vega GL, Grundy SM, Browning JD. Ethnic differences in hepatic steatosis: An insulin resistance paradox? Hepatology 49: 791‐801, 2009.
 99.Guillet‐Deniau I, Mieulet V, Le Lay S, Achouri Y, Carre D, Girard J, Foufelle F, Ferre P. Sterol regulatory element binding protein‐1c expression and action in rat muscles: Insulin‐like effects on the control of glycolytic and lipogenic enzymes and UCP3 gene expression. Diabetes 51: 1722‐1728, 2002.
 100.Gutierrez‐Juarez R, Pocai A, Mulas C, Ono H, Bhanot S, Monia BP, Rossetti L. Critical role of stearoyl‐CoA desaturase‐1 (SCD1) in the onset of diet‐induced hepatic insulin resistance. J Clin Invest 116: 1686‐1695, 2006.
 101.Hamaguchi M, Kojima T, Takeda N, Nakagawa T, Taniguchi H, Fujii K, Omatsu T, Nakajima T, Sarui H, Shimazaki M, Kato T, Okuda J, Ida K. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 143: 722‐728, 2005.
 102.Hamilton JA. How fatty acids bind to proteins: The inside story from protein structures. Prostaglandins Leukot Essent Fatty Acids 67: 65‐72, 2002.
 103.Hamilton JA. New insights into the roles of proteins and lipids in membrane transport of fatty acids. Prostaglandins Leukot Essent Fatty Acids 77: 355‐361, 2007.
 104.Hamilton JA, Johnson RA, Corkey B, Kamp F. Fatty acid transport: The diffusion mechanism in model and biological membranes. J Mol Neurosci 16: 99‐108, 2001.
 105.Hamilton JA, Kamp F. How are free fatty acids transported in membranes? Is it by proteins or by free diffusion through the lipids? Diabetes 48: 2255‐2269, 1999.
 106.Han MS, Lim YM, Quan W, Kim JR, Chung KW, Kang M, Kim S, Park SY, Han JS, Cheon HG, Dal Rhee S, Park TS, Lee MS. Lysophosphatidylcholine as an effector of fatty acid‐induced insulin resistance. J Lipid Res 52: 1234‐1246, 2011.
 107.Han MS, Park SY, Shinzawa K, Kim S, Chung KW, Lee JH, Kwon CH, Lee KW, Park CK, Chung WJ, Hwang JS, Yan JJ, Song DK, Tsujimoto Y, Lee MS. Lysophosphatidylcholine as a death effector in the lipoapoptosis of hepatocytes. J Lipid Res 49: 84‐97, 2008.
 108.Hardie DG. Minireview: The AMP‐activated protein kinase cascade: The key sensor of cellular energy status. Endocrinology 144: 5179‐5183, 2003.
 109.Hartman HB, Lai K, Evans MJ. Loss of small heterodimer partner expression in the liver protects against dyslipidemia. J Lipid Res 50: 193‐203, 2009.
 110.Hoekstra M, Lammers B, Out R, Li Z, Van Eck M, Van Berkel TJ. Activation of the nuclear receptor PXR decreases plasma LDL‐cholesterol levels and induces hepatic steatosis in LDL receptor knockout mice. Mol Pharm 6: 182‐189, 2009.
 111.Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res 52: 593‐617, 2011.
 112.Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci U S A 95: 5987‐5992, 1998.
 113.Horton JD, Goldstein JL, Brown MS. SREBPs: Activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 109: 1125‐1131, 2002.
 114.Horton JD, Goldstein JL, Brown MS. SREBPs: Transcriptional mediators of lipid homeostasis. Cold Spring Harb Symp Quant Biol 67: 491‐498, 2002.
 115.Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor‐alpha: Direct role in obesity‐linked insulin resistance. Science 259: 87‐91, 1993.
 116.Hua X, Wu J, Goldstein JL, Brown MS, Hobbs HH. Structure of the human gene encoding sterol regulatory element binding protein‐1 (SREBF1) and localization of SREBF1 and SREBF2 to chromosomes 17p11.2 and 22q13. Genomics 25: 667‐673, 1995.
 117.Huang J, Iqbal J, Saha PK, Liu J, Chan L, Hussain MM, Moore DD, Wang L. Molecular characterization of the role of orphan receptor small heterodimer partner in development of fatty liver. Hepatology 46: 147‐157, 2007.
 118.Huggins KW, Camarota LM, Howles PN, Hui DY. Pancreatic triglyceride lipase deficiency minimally affects dietary fat absorption but dramatically decreases dietary cholesterol absorption in mice. J Biol Chem 278: 42899‐42905, 2003.
 119.Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF‐alpha or adiponectin? Hepatology 40: 46‐54, 2004.
 120.Iizuka K, Bruick RK, Liang G, Horton JD, Uyeda K. Deficiency of carbohydrate response element‐binding protein (ChREBP) reduces lipogenesis as well as glycolysis. Proc Natl Acad Sci U S A 101: 7281‐7286, 2004.
 121.Iizuka K, Miller B, Uyeda K. Deficiency of carbohydrate‐activated transcription factor ChREBP prevents obesity and improves plasma glucose control in leptin‐deficient (ob/ob) mice. Am J Physiol Endocrinol Metab 291: E358‐E364, 2006.
 122.Inagaki T, Choi M, Moschetta A, Peng L, Cummins CL, McDonald JG, Luo G, Jones SA, Goodwin B, Richardson JA, Gerard RD, Repa JJ, Mangelsdorf DJ, Kliewer SA. Fibroblast growth factor 15 functions as an enterohepatic signal to regulate bile acid homeostasis. Cell Metab 2: 217‐225, 2005.
 123.Ip E, Farrell G, Hall P, Robertson G, Leclercq I. Administration of the potent PPARalpha agonist, Wy‐14,643, reverses nutritional fibrosis and steatohepatitis in mice. Hepatology 39: 1286‐1296, 2004.
 124.Iqbal J, Hussain MM. Intestinal lipid absorption. Am J Physiol Endocrinol Metab 296: E1183‐E1194, 2009.
 125.Ishii S, Iizuka K, Miller BC, Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci U S A 101: 15597‐15602, 2004.
 126.Jambunathan S, Yin J, Khan W, Tamori Y, Puri V. FSP27 promotes lipid droplet clustering and then fusion to regulate triglyceride accumulation. PLoS One 6: e28614, 2011.
 127.Joseph SB, Laffitte BA, Patel PH, Watson MA, Matsukuma KE, Walczak R, Collins JL, Osborne TF, Tontonoz P. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X receptors. J Biol Chem 277: 11019‐11025, 2002.
 128.Kakisaka K, Cazanave SC, Fingas CD, Guicciardi ME, Bronk SF, Werneburg NW, Mott JL, Gores GJ. Mechanisms of lysophosphatidylcholine‐induced hepatocyte lipoapoptosis. Am J Physiol Gastrointest Liver Physiol 302: G77‐G84, 2012.
 129.Kallwitz ER, McLachlan A, Cotler SJ. Role of peroxisome proliferators‐activated receptors in the pathogenesis and treatment of nonalcoholic fatty liver disease. World J Gastroenterol 14: 22‐28, 2008.
 130.Kamp F, Guo W, Souto R, Pilch PF, Corkey BE, Hamilton JA. Rapid flip‐flop of oleic acid across the plasma membrane of adipocytes. World J Gastroenterol 278: 7988‐7995, 2003.
 131.Kampf JP, Kleinfeld AM. Is membrane transport of FFA mediated by lipid, protein, or both? An unknown protein mediates free fatty acid transport across the adipocyte plasma membrane. Physiology (Bethesda) 22: 7‐14, 2007.
 132.Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons‐Romero F, Ebenbichler CF, Patsch JR, Tilg H. Adiponectin and its receptors in non‐alcoholic steatohepatitis. Gut 54: 117‐121, 2005.
 133.Keller P, Petrie JT, De Rose P, Gerin I, Wright WS, Chiang SH, Nielsen AR, Fischer CP, Pedersen BK, MacDougald OA. Fat‐specific protein 27 regulates storage of triacylglycerol. J Biol Chem 283: 14355‐14365, 2008.
 134.Kerr TA, Saeki S, Schneider M, Schaefer K, Berdy S, Redder T, Shan B, Russell DW, Schwarz M. Loss of nuclear receptor SHP impairs but does not eliminate negative feedback regulation of bile acid synthesis. Dev Cell 2: 713‐720, 2002.
 135.Kim JB, Sarraf P, Wright M, Yao KM, Mueller E, Solanes G, Lowell BB, Spiegelman BM. Nutritional and insulin regulation of fatty acid synthetase and leptin gene expression through ADD1/SREBP1. J Clin Invest 101: 1‐9, 1998.
 136.Kimmel AR, Brasaemle DL, McAndrews‐Hill M, Sztalryd C, Londos C. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT‐family of intracellular lipid storage droplet proteins. J Lipid Res 51: 468‐471, 2010.
 137.Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp‐Arida A, Yeh M, McCullough AJ, Sanyal AJ. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 41: 1313‐1321, 2005.
 138.Kleinfeld AM. Lipid phase fatty acid flip‐flop, is it fast enough for cellular transport? J Membr Biol 175: 79‐86, 2000.
 139.Kodama S, Koike C, Negishi M, Yamamoto Y. Nuclear receptors CAR and PXR cross talk with FOXO1 to regulate genes that encode drug‐metabolizing and gluconeogenic enzymes. Mol Cell Biol 24: 7931‐7940, 2004.
 140.Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Takayanagi R, Nakamuta M. Re‐evaluation of fatty acid metabolism‐related gene expression in nonalcoholic fatty liver disease. Int J Mol Med 20: 351‐358, 2007.
 141.Korenblat KM, Fabbrini E, Mohammed BS, Klein S. Liver, muscle, and adipose tissue insulin action is directly related to intrahepatic triglyceride content in obese subjects. Gastroenterology 134: 1369‐1375, 2008.
 142.Kovsan J, Bluher M, Tarnovscki T, Kloting N, Kirshtein B, Madar L, Shai I, Golan R, Harman‐Boehm I, Schon MR, Greenberg AS, Elazar Z, Bashan N, Rudich A. Altered autophagy in human adipose tissues in obesity. J Clin Endocrinol Metab 96: E268‐E277, 2011.
 143.Krawczyk M, Bonfrate L, Portincasa P. Nonalcoholic fatty liver disease. Best Pract Res Clin Gastroenterol 24: 695‐708, 2010.
 144.Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 108: 16381‐16385, 2011.
 145.Lake AC, Sun Y, Li JL, Kim JE, Johnson JW, Li D, Revett T, Shih HH, Liu W, Paulsen JE, Gimeno RE. Expression, regulation, and triglyceride hydrolase activity of Adiponutrin family members. J Lipid Res 46: 2477‐2487, 2005.
 146.Lambert JE, Parks EJ. Postprandial metabolism of meal triglyceride in humans. Biochim Biophys Acta 1821: 721‐726, 2012.
 147.Lammert F, Wang DQ. New insights into the genetic regulation of intestinal cholesterol absorption. Gastroenterology 129: 718‐734, 2005.
 148.Le Lay S, Dugail I. Connecting lipid droplet biology and the metabolic syndrome. Prog Lipid Res 48: 191‐195, 2009.
 149.Lee YS, Chanda D, Sim J, Park YY, Choi HS. Structure and function of the atypical orphan nuclear receptor small heterodimer partner. Int Rev Cytol 261: 117‐158, 2007.
 150.Lefebvre P, Cariou B, Lien F, Kuipers F, Staels B. Role of bile acids and bile acid receptors in metabolic regulation. Physiol Rev 89: 147‐191, 2009.
 151.Lefebvre P, Chinetti G, Fruchart JC, Staels B. Sorting out the roles of PPAR alpha in energy metabolism and vascular homeostasis. J Clin Invest 116: 571‐580, 2006.
 152.Levene AP, Goldin RD. The epidemiology, pathogenesis and histopathology of fatty liver disease. Histopathology 61: 141‐152, 2012.
 153.Lewis GF. Fatty acid regulation of very low density lipoprotein production. Curr Opin Lipidol 8: 146‐153, 1997.
 154.Li JZ, Lei Y, Wang Y, Zhang Y, Ye J, Xia X, Pan X, Li P. Control of cholesterol biosynthesis, uptake and storage in hepatocytes by Cideb. Biochim Biophys Acta 1801: 577‐586, 2010.
 155.Li JZ, Ye J, Xue B, Qi J, Zhang J, Zhou Z, Li Q, Wen Z, Li P. Cideb regulates diet‐induced obesity, liver steatosis, and insulin sensitivity by controlling lipogenesis and fatty acid oxidation. Diabetes 56: 2523‐2532, 2007.
 156.Li MV, Chang B, Imamura M, Poungvarin N, Chan L. Glucose‐dependent transcriptional regulation by an evolutionarily conserved glucose‐sensing module. Diabetes 55: 1179‐1189, 2006.
 157.Li Z, Vance DE. Phosphatidylcholine and choline homeostasis. J Lipid Res 49: 1187‐1194, 2008.
 158.Liang G, Yang J, Horton JD, Hammer RE, Goldstein JL, Brown MS. Diminished hepatic response to fasting/refeeding and liver X receptor agonists in mice with selective deficiency of sterol regulatory element‐binding protein‐1c. J Biol Chem 277: 9520‐9528, 2002.
 159.Liao YJ, Liu SP, Lee CM, Yen CH, Chuang PC, Chen CY, Tsai TF, Huang SF, Lee YH, Chen YM. Characterization of a glycine N‐methyltransferase gene knockout mouse model for hepatocellular carcinoma: Implications of the gender disparity in liver cancer susceptibility. Int J Cancer 124: 816‐826, 2009.
 160.Lim JS, Mietus‐Snyder M, Valente A, Schwarz JM, Lustig RH. The role of fructose in the pathogenesis of NAFLD and the metabolic syndrome. Nat Rev Gastroenterol Hepatol 7: 251‐264, 2010.
 161.Listenberger LL, Han X, Lewis SE, Cases S, Farese RV, Jr., Ory DS, Schaffer JE. Triglyceride accumulation protects against fatty acid‐induced lipotoxicity. Proc Natl Acad Sci U S A 100: 3077‐3082, 2003.
 162.Liu YM, Moldes M, Bastard JP, Bruckert E, Viguerie N, Hainque B, Basdevant A, Langin D, Pairault J, Clement K. Adiponutrin: A new gene regulated by energy balance in human adipose tissue. J Clin Endocrinol Metab 89: 2684‐2689, 2004.
 163.Lomonaco R, Ortiz‐Lopez C, Orsak B, Webb A, Hardies J, Darland C, Finch J, Gastaldelli A, Harrison S, Tio F, Cusi K. Effect of adipose tissue insulin resistance on metabolic parameters and liver histology in obese patients with nonalcoholic fatty liver disease. Hepatology 55: 1389‐1397, 2012.
 164.Lopez‐Velazquez JA, Carrillo‐Cordova LD, Chavez‐Tapia NC, Uribe M, Mendez‐Sanchez N. Nuclear receptors in nonalcoholic Fatty liver disease. J Lipids 2012: 139875, 2012.
 165.Lu SC, Alvarez L, Huang ZZ, Chen L, An W, Corrales FJ, Avila MA, Kanel G, Mato JM. Methionine adenosyltransferase 1A knockout mice are predisposed to liver injury and exhibit increased expression of genes involved in proliferation. Proc Natl Acad Sci U S A 98: 5560‐5565, 2001.
 166.Lu SC, Mato JM. S‐adenosylmethionine in liver health, injury, and cancer. Physiol Rev 92: 1515‐1542, 2012.
 167.Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6: 507‐515, 2000.
 168.Lu X, Gruia‐Gray J, Copeland NG, Gilbert DJ, Jenkins NA, Londos C, Kimmel AR. The murine perilipin gene: The lipid droplet‐associated perilipins derive from tissue‐specific, mRNA splice variants and define a gene family of ancient origin. Mamm Genome 12: 741‐749, 2001.
 169.Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 55: 434‐438, 1980.
 170.Luka Z, Capdevila A, Mato JM, Wagner C. A glycine N‐methyltransferase knockout mouse model for humans with deficiency of this enzyme. Transgenic Res 15: 393‐397, 2006.
 171.Luka Z, Cerone R, Phillips JA, III, Mudd HS, Wagner C. Mutations in human glycine N‐methyltransferase give insights into its role in methionine metabolism. Hum Genet 110: 68‐74, 2002.
 172.Ma K, Saha PK, Chan L, Moore DD. Farnesoid X receptor is essential for normal glucose homeostasis. J Clin Invest 116: 1102‐1109, 2006.
 173.Maeda N, Takahashi M, Funahashi T, Kihara S, Nishizawa H, Kishida K, Nagaretani H, Matsuda M, Komuro R, Ouchi N, Kuriyama H, Hotta K, Nakamura T, Shimomura I, Matsuzawa Y. PPARgamma ligands increase expression and plasma concentrations of adiponectin, an adipose‐derived protein. Diabetes 50: 2094‐2099, 2001.
 174.Maldonado‐Valderrama J, Wilde P, Macierzanka A, Mackie A. The role of bile salts in digestion. Adv Colloid Interface Sci 165: 36‐46, 2011.
 175.Malhi H, Gores GJ. Molecular mechanisms of lipotoxicity in nonalcoholic fatty liver disease. Semin Liver Dis 28: 360‐369, 2008.
 176.Mansbach CM, Siddiqi SA. The biogenesis of chylomicrons. Annu Rev Physiol 72: 315‐333, 2010.
 177.Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, Melchionda N. Nonalcoholic fatty liver disease: A feature of the metabolic syndrome. Diabetes 50: 1844‐1850, 2001.
 178.Marra F, Efsen E, Romanelli RG, Caligiuri A, Pastacaldi S, Batignani G, Bonacchi A, Caporale R, Laffi G, Pinzani M, Gentilini P. Ligands of peroxisome proliferator‐activated receptor gamma modulate profibrogenic and proinflammatory actions in hepatic stellate cells. Gastroenterology 119: 466‐478, 2000.
 179.Martinez‐Chantar ML, Corrales FJ, Martinez‐Cruz LA, Garcia‐Trevijano ER, Huang ZZ, Chen L, Kanel G, Avila MA, Mato JM, Lu SC. Spontaneous oxidative stress and liver tumors in mice lacking methionine adenosyltransferase 1A. FASEB J 16: 1292‐1294, 2002.
 180.Martinez‐Chantar ML, Vazquez‐Chantada M, Ariz U, Martinez N, Varela M, Luka Z, Capdevila A, Rodriguez J, Aransay AM, Matthiesen R, Yang H, Calvisi DF, Esteller M, Fraga M, Lu SC, Wagner C, Mato JM. Loss of the glycine N‐methyltransferase gene leads to steatosis and hepatocellular carcinoma in mice. Hepatology 47: 1191‐1199, 2008.
 181.Martinez‐Lopez N, Varela‐Rey M, Ariz U, Embade N, Vazquez‐Chantada M, Fernandez‐Ramos D, Gomez‐Santos L, Lu SC, Mato JM, Martinez‐Chantar ML. S‐adenosylmethionine and proliferation: New pathways, new targets. Biochem Soc Trans 36: 848‐852, 2008.
 182.Mato JM, Alvarez L, Ortiz P, Pajares MA. S‐adenosylmethionine synthesis: Molecular mechanisms and clinical implications. Pharmacol Ther 73: 265‐280, 1997.
 183.Mato JM, Martinez‐Chantar ML, Lu SC. Methionine metabolism and liver disease. Ann Rev Nutr 28: 273‐293, 2008.
 184.Mato JM, Martinez‐Chantar ML, Lu SC. S‐adenosylmethionine metabolism and liver disease. Ann Hepatol 12: 183‐189, 2013.
 185.Matsusue K, Kusakabe T, Noguchi T, Takiguchi S, Suzuki T, Yamano S, Gonzalez FJ. Hepatic steatosis in leptin‐deficient mice is promoted by the PPARgamma target gene Fsp27. Cell Metab 7: 302‐311, 2008.
 186.Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: A spectrum of clinical and pathological severity. Gastroenterology 116: 1413‐1419, 1999.
 187.Meunier‐Durmort C, Poirier H, Niot I, Forest C, Besnard P. Up‐regulation of the expression of the gene for liver fatty acid‐binding protein by long‐chain fatty acids. Biochem J 319: 483‐487, 1996.
 188.Miao J, Choi SE, Seok SM, Yang L, Zuercher WJ, Xu Y, Willson TM, Xu HE, Kemper JK. Ligand‐dependent regulation of the activity of the orphan nuclear receptor, small heterodimer partner (SHP), in the repression of bile acid biosynthetic CYP7A1 and CYP8B1 genes. Mol Endocrinol 25: 1159‐1169, 2011.
 189.Miao J, Fang S, Bae Y, Kemper JK. Functional inhibitory cross‐talk between constitutive androstane receptor and hepatic nuclear factor‐4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP‐1 and PGC‐1alpha. J Biol Chem 281: 14537‐14546, 2006.
 190.Minokoshi Y, Kim YB, Peroni OD, Fryer LG, Muller C, Carling D, Kahn BB. Leptin stimulates fatty‐acid oxidation by activating AMP‐activated protein kinase. Nature 415: 339‐343, 2002.
 191.Mitro N, Mak PA, Vargas L, Godio C, Hampton E, Molteni V, Kreusch A, Saez E. The nuclear receptor LXR is a glucose sensor. Nature 445: 219‐223, 2007.
 192.Miura S, Gan JW, Brzostowski J, Parisi MJ, Schultz CJ, Londos C, Oliver B, Kimmel AR. Functional conservation for lipid storage droplet association among Perilipin, ADRP, and TIP47 (PAT)‐related proteins in mammals, Drosophila, and Dictyostelium. J Biol Chem 277: 32253‐32257, 2002.
 193.Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab 87: 2784‐2791, 2002.
 194.Miyazaki Y, Matsuda M, DeFronzo RA. Dose‐response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes care 25: 517‐523, 2002.
 195.Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV, Sr., Hevener AL, Farese RV, Jr. Dissociation of hepatic steatosis and insulin resistance in mice overexpressing DGAT in the liver. Cell Metab 6: 69‐78, 2007.
 196.Mori TA, Bao DQ, Burke V, Puddey IB, Watts GF, Beilin LJ. Dietary fish as a major component of a weight‐loss diet: Effect on serum lipids, glucose, and insulin metabolism in overweight hypertensive subjects. Am J Clin Nutr 70: 817‐825, 1999.
 197.Mori TA, Dunstan DW, Burke V, Croft KD, Rivera JH, Beilin LJ, Puddey IB. Effect of dietary fish and exercise training on urinary F2‐isoprostane excretion in non‐insulin‐dependent diabetic patients. Metabolism 48: 1402‐1408, 1999.
 198.Morral N, Edenberg HJ, Witting SR, Altomonte J, Chu T, Brown M. Effects of glucose metabolism on the regulation of genes of fatty acid synthesis and triglyceride secretion in the liver. J Lipid Res 48: 1499‐1510, 2007.
 199.Mu H, Hoy CE. The digestion of dietary triacylglycerols. Prog Lipid Res 43: 105‐133, 2004.
 200.Mudd SH, Cerone R, Schiaffino MC, Fantasia AR, Minniti G, Caruso U, Lorini R, Watkins D, Matiaszuk N, Rosenblatt DS, Schwahn B, Rozen R, LeGros L, Kotb M, Capdevila A, Luka Z, Finkelstein JD, Tangerman A, Stabler SP, Allen RH, Wagner C. Glycine N‐methyltransferase deficiency: A novel inborn error causing persistent isolated hypermethioninaemia. J Inherit Metab Dis 24: 448‐464, 2001.
 201.Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non‐alcoholic fatty liver disease (NAFLD). Prog Lipid Res 48: 1‐26, 2009.
 202.Musso G, Gambino R, Durazzo M, Biroli G, Carello M, Faga E, Pacini G, De Michieli F, Rabbione L, Premoli A, Cassader M, Pagano G. Adipokines in NASH: Postprandial lipid metabolism as a link between adiponectin and liver disease. Hepatology 42: 1175‐1183, 2005.
 203.Nagasawa T, Inada Y, Nakano S, Tamura T, Takahashi T, Maruyama K, Yamazaki Y, Kuroda J, Shibata N. Effects of bezafibrate, PPAR pan‐agonist, and GW501516, PPARdelta agonist, on development of steatohepatitis in mice fed a methionine‐ and choline‐deficient diet. Eur J Pharmacol 536: 182‐191, 2006.
 204.Nagle CA, An J, Shiota M, Torres TP, Cline GW, Liu ZX, Wang S, Catlin RL, Shulman GI, Newgard CB, Coleman RA. Hepatic overexpression of glycerol‐sn‐3‐phosphate acyltransferase 1 in rats causes insulin resistance. J Biol Chem 282: 14807‐14815, 2007.
 205.Nakamura K, Moore R, Negishi M, Sueyoshi T. Nuclear pregnane X receptor cross‐talk with FoxA2 to mediate drug‐induced regulation of lipid metabolism in fasting mouse liver. J Biol Chem 282: 9768‐9776, 2007.
 206.Nakatani T, Katsumata A, Miura S, Kamei Y, Ezaki O. Effects of fish oil feeding and fasting on LXRalpha/RXRalpha binding to LXRE in the SREBP‐1c promoter in mouse liver. Biochim Biophys Acta 1736: 77‐86, 2005.
 207.Namikawa C, Shu‐Ping Z, Vyselaar JR, Nozaki Y, Nemoto Y, Ono M, Akisawa N, Saibara T, Hiroi M, Enzan H, Onishi S. Polymorphisms of microsomal triglyceride transfer protein gene and manganese superoxide dismutase gene in non‐alcoholic steatohepatitis. J Hepatol 40: 781‐786, 2004.
 208.Neuschwander‐Tetri BA. Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: The central role of nontriglyceride fatty acid metabolites. Hepatology 52: 774‐788, 2010.
 209.Neuschwander‐Tetri BA. Nontriglyceride hepatic lipotoxicity: The new paradigm for the pathogenesis of NASH. Curr Gastroenterol Rep 12: 49‐56, 2010.
 210.Neuschwander‐Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR‐gamma ligand rosiglitazone. Hepatology 38: 1008‐1017, 2003.
 211.Neuschwander‐Tetri BA, Brunt EM, Wehmeier KR, Sponseller CA, Hampton K, Bacon BR. Interim results of a pilot study demonstrating the early effects of the PPAR‐gamma ligand rosiglitazone on insulin sensitivity, aminotransferases, hepatic steatosis and body weight in patients with non‐alcoholic steatohepatitis. J Hepatol 38: 434‐440, 2003.
 212.Neuschwander‐Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: Summary of an AASLD Single Topic Conference. Hepatology 37: 1202‐1219, 2003.
 213.Nguyen‐Duy TB, Nichaman MZ, Church TS, Blair SN, Ross R. Visceral fat and liver fat are independent predictors of metabolic risk factors in men. Am J Physiol Endocrinol Metab 284: E1065‐E1071, 2003.
 214.Nguyen TA, Sanyal AJ. Pathophysiology guided treatment of nonalcoholic steatohepatitis. J Gastroenterol Hepatol 27(Suppl 2): 58‐64, 2012.
 215.Nielsen S, Guo Z, Johnson CM, Hensrud DD, Jensen MD. Splanchnic lipolysis in human obesity. J Clin Invest 113: 1582‐1588, 2004.
 216.Niot I, Poirier H, Tran TT, Besnard P. Intestinal absorption of long‐chain fatty acids: Evidence and uncertainties. Prog Lipid Res 48: 101‐115, 2009.
 217.Nishino N, Tamori Y, Tateya S, Kawaguchi T, Shibakusa T, Mizunoya W, Inoue K, Kitazawa R, Kitazawa S, Matsuki Y, Hiramatsu R, Masubuchi S, Omachi A, Kimura K, Saito M, Amo T, Ohta S, Yamaguchi T, Osumi T, Cheng J, Fujimoto T, Nakao H, Nakao K, Aiba A, Okamura H, Fushiki T, Kasuga M. FSP27 contributes to efficient energy storage in murine white adipocytes by promoting the formation of unilocular lipid droplets. J Clin Invest 118: 2808‐2821, 2008.
 218.Nordstrom EA, Ryden M, Backlund EC, Dahlman I, Kaaman M, Blomqvist L, Cannon B, Nedergaard J, Arner P. A human‐specific role of cell death‐inducing DFFA (DNA fragmentation factor‐alpha)‐like effector A (CIDEA) in adipocyte lipolysis and obesity. Diabetes 54: 1726‐1734, 2005.
 219.Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD. Loss of stearoyl‐CoA desaturase‐1 function protects mice against adiposity. Proc Natl Acad Sci U S A 99: 11482‐11486, 2002.
 220.Olofsson SO, Bostrom P, Andersson L, Rutberg M, Perman J, Boren J. Lipid droplets as dynamic organelles connecting storage and efflux of lipids. Biochim Biophys Acta 1791: 448‐458, 2009.
 221.Ou J, Tu H, Shan B, Luk A, DeBose‐Boyd RA, Bashmakov Y, Goldstein JL, Brown MS. Unsaturated fatty acids inhibit transcription of the sterol regulatory element‐binding protein‐1c (SREBP‐1c) gene by antagonizing ligand‐dependent activation of the LXR. Proc Natl Acad Sci U S A 98: 6027‐6032, 2001.
 222.Pai JT, Guryev O, Brown MS, Goldstein JL. Differential stimulation of cholesterol and unsaturated fatty acid biosynthesis in cells expressing individual nuclear sterol regulatory element‐binding proteins. J Biol Chem 273: 26138‐26148, 1998.
 223.Pardina E, Baena‐Fustegueras JA, Catalan R, Galard R, Lecube A, Fort JM, Allende H, Vargas V, Peinado‐Onsurbe J. Increased expression and activity of hepatic lipase in the liver of morbidly obese adult patients in relation to lipid content. Obes Surg 19: 894‐904, 2009.
 224.Park YJ, Kim SC, Kim J, Anakk S, Lee JM, Tseng HT, Yechoor V, Park J, Choi JS, Jang HC, Lee KU, Novak CM, Moore DD, Lee YK. Dissociation of diabetes and obesity in mice lacking orphan nuclear receptor small heterodimer partner. J Lipid Res 52: 2234‐2244, 2011.
 225.Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, Cline GW, Befroy D, Zemany L, Kahn BB, Papademetris X, Rothman DL, Shulman GI. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 104: 12587‐12594, 2007.
 226.Poirier H, Degrace P, Niot I, Bernard A, Besnard P. Localization and regulation of the putative membrane fatty‐acid transporter (FAT) in the small intestine. Comparison with fatty acid‐binding proteins (FABP). Eur J Biochem 238: 368‐373, 1996.
 227.Postic C, Dentin R, Girard J. Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab 30: 398‐408, 2004.
 228.Powell EE, Cooksley WG, Hanson R, Searle J, Halliday JW, Powell LW. The natural history of nonalcoholic steatohepatitis: A follow‐up study of forty‐two patients for up to 21 years. Hepatology 11: 74‐80, 1990.
 229.Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, Ghany M, Premkumar A, Park Y, Liang TJ, Yanovski JA, Kleiner DE, Hoofnagle JH. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology 39: 188‐196, 2004.
 230.Puri P, Baillie RA, Wiest MM, Mirshahi F, Choudhury J, Cheung O, Sargeant C, Contos MJ, Sanyal AJ. A lipidomic analysis of nonalcoholic fatty liver disease. Hepatology 46: 1081‐1090, 2007.
 231.Puri V, Konda S, Ranjit S, Aouadi M, Chawla A, Chouinard M, Chakladar A, Czech MP. Fat‐specific protein 27, a novel lipid droplet protein that enhances triglyceride storage. J Biol Chem 282: 34213‐34218, 2007.
 232.Puri V, Ranjit S, Konda S, Nicoloro SM, Straubhaar J, Chawla A, Chouinard M, Lin C, Burkart A, Corvera S, Perugini RA, Czech MP. Cidea is associated with lipid droplets and insulin sensitivity in humans. Proc Natl Acad Sci U S A 105: 7833‐7838, 2008.
 233.Rao MS, Reddy JK. PPARalpha in the pathogenesis of fatty liver disease. Hepatology 40: 783‐786, 2004.
 234.Ravikumar B, Carey PE, Snaar JE, Deelchand DK, Cook DB, Neely RD, English PT, Firbank MJ, Morris PG, Taylor R. Real‐time assessment of postprandial fat storage in liver and skeletal muscle in health and type 2 diabetes. Am J Physiol Endocrinol Metab 288: E789‐E797, 2005.
 235.Reddy JK, Hashimoto T. Peroxisomal beta‐oxidation and peroxisome proliferator‐activated receptor alpha: An adaptive metabolic system. Ann Rev Nutr 21: 193‐230, 2001.
 236.Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Annu Rev Nutr 290: G852‐G858, 2006.
 237.Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 40: 1461‐1465, 2008.
 238.Sabesin SM, Frase S. Electron microscopic studies of the assembly, intracellular transport, and secretion of chylomicrons by rat intestine. J Lipid Res 18: 496‐511, 1977.
 239.Sanyal AJ. Insulin resistance and nonalcoholic steatohepatitis: Fat or fiction? Am J Gastroenterol 96: 274‐276, 2001.
 240.Sanyal AJ, Campbell‐Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: Association of insulin resistance and mitochondrial abnormalities. Gastroenterology 120: 1183‐1192, 2001.
 241.Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander‐Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 362: 1675‐1685, 2010.
 242.Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG, Bhanot S, Monia BP, Shulman GI. Reversal of diet‐induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl‐CoA carboxylases 1 and 2. J Clin Invest 116: 817‐824, 2006.
 243.Savage DB, Petersen KF, Shulman GI. Disordered lipid metabolism and the pathogenesis of insulin resistance. Physiol Rev 87: 507‐520, 2007.
 244.Schaffer JE. Lipotoxicity: When tissues overeat. Curr Opin Lipidol 14: 281‐287, 2003.
 245.Schenk S, Saberi M, Olefsky JM. Insulin sensitivity: Modulation by nutrients and inflammation. J Clin Invest 118: 2992‐3002, 2008.
 246.Schonfeld G, Patterson BW, Yablonskiy DA, Tanoli TS, Averna M, Elias N, Yue P, Ackerman J. Fatty liver in familial hypobetalipoproteinemia: Triglyceride assembly into VLDL particles is affected by the extent of hepatic steatosis. J Lipid Res 44: 470‐478, 2003.
 247.Schreurs M, Kuipers F, van der Leij FR. Regulatory enzymes of mitochondrial beta‐oxidation as targets for treatment of the metabolic syndrome. Obes Rev 11: 380‐388, 2010.
 248.Schultz JR, Tu H, Luk A, Repa JJ, Medina JC, Li L, Schwendner S, Wang S, Thoolen M, Mangelsdorf DJ, Lustig KD, Shan B. Role of LXRs in control of lipogenesis. Genes Dev 14: 2831‐2838, 2000.
 249.Schwenk RW, Holloway GP, Luiken JJ, Bonen A, Glatz JF. Fatty acid transport across the cell membrane: Regulation by fatty acid transporters. Prostaglandins Leukot Essent Fatty Acids 82: 149‐154, 2010.
 250.Seol W, Choi HS, Moore DD. An orphan nuclear hormone receptor that lacks a DNA binding domain and heterodimerizes with other receptors. Science 272: 1336‐1339, 1996.
 251.Seppala‐Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, Halavaara J, Yki‐Jarvinen H. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab 87: 3023‐3028, 2002.
 252.U.S. Department of Agriculture and U.S. Department Health and Human Services. Dietary Guidelines for Americans. Gardiner, Maine: Northern House Media, 2011, p. 1‐95.
 253.She H, Xiong S, Hazra S, Tsukamoto H. Adipogenic transcriptional regulation of hepatic stellate cells. J Biol Chem 280: 4959‐4967, 2005.
 254.Sheth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 126: 137‐145, 1997.
 255.Shi Y, Cheng D. Beyond triglyceride synthesis: The dynamic functional roles of MGAT and DGAT enzymes in energy metabolism. Am J Physiol Endocrinol Metab 297: E10‐E18, 2009.
 256.Shimano H, Horton JD, Shimomura I, Hammer RE, Brown MS, Goldstein JL. Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells. J Clin Invest 99: 846‐854, 1997.
 257.Shimomura I, Bashmakov Y, Horton JD. Increased levels of nuclear SREBP‐1c associated with fatty livers in two mouse models of diabetes mellitus. J Biol Chem 274: 30028‐30032, 1999.
 258.Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP‐1c mRNA in the livers of rats with streptozotocin‐induced diabetes. Proc Natl Acad Sci U S A 96: 13656‐13661, 1999.
 259.Shimomura I, Shimano H, Horton JD, Goldstein JL, Brown MS. Differential expression of exons 1a and 1c in mRNAs for sterol regulatory element binding protein‐1 in human and mouse organs and cultured cells. J Clin Invest 99: 838‐845, 1997.
 260.Shimomura I, Shimano H, Korn BS, Bashmakov Y, Horton JD. Nuclear sterol regulatory element‐binding proteins activate genes responsible for the entire program of unsaturated fatty acid biosynthesis in transgenic mouse liver. J Biol Chem 273: 35299‐35306, 1998.
 261.Singh H, Ye A, Horne D. Structuring food emulsions in the gastrointestinal tract to modify lipid digestion. Prog Lipid Res 48: 92‐100, 2009.
 262.Singh R, Cuervo AM. Lipophagy: Connecting autophagy and lipid metabolism. Int J Cell Biol 2012: 282041, 2012.
 263.Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature 458: 1131‐1135, 2009.
 264.Stahl A, Hirsch DJ, Gimeno RE, Punreddy S, Ge P, Watson N, Patel S, Kotler M, Raimondi A, Tartaglia LA, Lodish HF. Identification of the major intestinal fatty acid transport protein. Mol Cell 4: 299‐308, 1999.
 265.Staudinger JL, Goodwin B, Jones SA, Hawkins‐Brown D, MacKenzie KI, LaTour A, Liu Y, Klaassen CD, Brown KK, Reinhard J, Willson TM, Koller BH, Kliewer SA. The nuclear receptor PXR is a lithocholic acid sensor that protects against liver toxicity. Proc Natl Acad Sci U S A 98: 3369‐3374, 2001.
 266.Stefanovic‐Racic M, Perdomo G, Mantell BS, Sipula IJ, Brown NF, O'Doherty RM. A moderate increase in carnitine palmitoyltransferase 1a activity is sufficient to substantially reduce hepatic triglyceride levels. Am J Physiol Endocrinol Metab 294: E969‐E977, 2008.
 267.Stoeckman AK, Towle HC. The role of SREBP‐1c in nutritional regulation of lipogenic enzyme gene expression. J Biol Chem 277: 27029‐27035, 2002.
 268.Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: Prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 288: E462‐E468, 2005.
 269.Szendroedi J, Chmelik M, Schmid AI, Nowotny P, Brehm A, Krssak M, Moser E, Roden M. Abnormal hepatic energy homeostasis in type 2 diabetes. Hepatology 50: 1079‐1086, 2009.
 270.Tabbi‐Anneni I, Cooksey R, Gunda V, Liu S, Mueller A, Song G, McClain DA, Wang L. Overexpression of nuclear receptor SHP in adipose tissues affects diet‐induced obesity and adaptive thermogenesis. Am J Physiol Endocrinol Metab 298: E961‐E970, 2010.
 271.Tamura S, Shimomura I. Contribution of adipose tissue and de novo lipogenesis to nonalcoholic fatty liver disease. J Clin Invest 115: 1139‐1142, 2005.
 272.Targher G, Day CP, Bonora E. Risk of cardiovascular disease in patients with nonalcoholic fatty liver disease. N Engl J Med 363: 1341‐1350, 2010.
 273.Tauchi‐Sato K, Ozeki S, Houjou T, Taguchi R, Fujimoto T. The surface of lipid droplets is a phospholipid monolayer with a unique Fatty Acid composition. J Biol Chem 277: 44507‐44512, 2002.
 274.Teli MR, James OF, Burt AD, Bennett MK, Day CP. The natural history of nonalcoholic fatty liver: A follow‐up study. Hepatology 22: 1714‐1719, 1995.
 275.Tetri LH, Basaranoglu M, Brunt EM, Yerian LM, Neuschwander‐Tetri BA. Severe NAFLD with hepatic necroinflammatory changes in mice fed trans fats and a high‐fructose corn syrup equivalent. Am J Physiol Gastrointest Liver Physiol 295: G987‐G995, 2008.
 276.Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 6: 772‐783, 2006.
 277.Tilg H, Moschen AR. Insulin resistance, inflammation, and non‐alcoholic fatty liver disease. Trends Endocrinol Metab 19: 371‐379, 2008.
 278.Timsit YE, Negishi M. CAR and PXR: The xenobiotic‐sensing receptors. Steroids 72: 231‐246, 2007.
 279.Toh SY, Gong J, Du G, Li JZ, Yang S, Ye J, Yao H, Zhang Y, Xue B, Li Q, Yang H, Wen Z, Li P. Up‐regulation of mitochondrial activity and acquirement of brown adipose tissue‐like property in the white adipose tissue of fsp27 deficient mice. PLoS One 3: e2890, 2008.
 280.Trigatti BL, Gerber GE. The effect of intracellular pH on long‐chain fatty acid uptake in 3T3‐L1 adipocytes: Evidence that uptake involves the passive diffusion of protonated long‐chain fatty acids across the plasma membrane. Biochem J 313: 487‐494, 1996.
 281.Tsatsos NG, Towle HC. Glucose activation of ChREBP in hepatocytes occurs via a two‐step mechanism. Biochem Biophys Res Commun 340: 449‐456, 2006.
 282.Tso P, Balint JA. Formation and transport of chylomicrons by enterocytes to the lymphatics. Am J Physiol Gastrointest Liver Physiol 250: G715‐G726, 1986.
 283.Unger RH. Lipotoxic diseases. Annu Rev Med 53: 319‐336, 2002.
 284.Unger RH. Minireview: Weapons of lean body mass destruction: The role of ectopic lipids in the metabolic syndrome. Endocrinology 144: 5159‐5165, 2003.
 285.Uppal H, Toma D, Saini SP, Ren S, Jones TJ, Xie W. Combined loss of orphan receptors PXR and CAR heightens sensitivity to toxic bile acids in mice. Hepatology 41: 168‐176, 2005.
 286.Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab 4: 107‐110, 2006.
 287.Valenti L, Rametta R, Dongiovanni P, Maggioni M, Fracanzani AL, Zappa M, Lattuada E, Roviaro G, Fargion S. Increased expression and activity of the transcription factor FOXO1 in nonalcoholic steatohepatitis. Diabetes 57: 1355‐1362, 2008.
 288.van Herpen NA, Schrauwen‐Hinderling VB. Lipid accumulation in non‐adipose tissue and lipotoxicity. Physiol Behav 94: 231‐241, 2008.
 289.Vinciguerra M, Veyrat‐Durebex C, Moukil MA, Rubbia‐Brandt L, Rohner‐Jeanrenaud F, Foti M. PTEN down‐regulation by unsaturated fatty acids triggers hepatic steatosis via an NF‐kappaBp65/mTOR‐dependent mechanism. Gastroenterology 134: 268‐280, 2008.
 290.Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endoplasmic reticulum stress and liver injury in rats with hepatic steatosis. Endocrinology 147: 943‐951, 2006.
 291.Wang DQ. Regulation of intestinal cholesterol absorption. Annu Rev Physiol 69: 221‐248, 2007.
 292.Wang DQ, Cohen DE. Absorption and excretion of cholesterol and other sterols. In: Ballantyne CM, editor. Lipidology in the Treatment and Prevention of Cardiovascular Disease (Clinical Lipidology: A Companion to Braunwald's Heart Disease). Philadelphia: Elsevier Saunders, 2008, pp. 26‐44.
 293.Wang DQ, Lammert F, Cohen DE, Paigen B, Carey MC. Cholic acid aids absorption, biliary secretion, and phase transitions of cholesterol in murine cholelithogenesis. Am J Physiol Gastrointest Liver Physiol 276: G751‐G760, 1999.
 294.Wang DQ, Neuschwander‐Tetri BA, Portincasa P. The Biliary System. Princeton, New Jersey: Morgan & Claypool Life Sciences, 2012, pp. 1‐146.
 295.Wang DQ, Tazuma S, Cohen DE, Carey MC. Feeding natural hydrophilic bile acids inhibits intestinal cholesterol absorption: Studies in the gallstone‐susceptible mouse. Am J Physiol Gastrointest Liver Physiol 285: G494‐G502, 2003.
 296.Wang HH, Afdhal NH, Gendler SJ, Wang DQ. Lack of the intestinal Muc1 mucin impairs cholesterol uptake and absorption but not fatty acid uptake in Muc1−/− mice. Am J Physiol Gastrointest Liver Physiol 287: G547‐G554, 2004.
 297.Wang HH, Portincasa P, Wang DQ. Molecular pathophysiology and physical chemistry of cholesterol gallstones. Front Biosci 13: 401‐423, 2008.
 298.Wang L, Liu J, Saha P, Huang J, Chan L, Spiegelman B, Moore DD. The orphan nuclear receptor SHP regulates PGC‐1alpha expression and energy production in brown adipocytes. Cell Metab 2: 227‐238, 2005.
 299.Wang YD, Chen WD, Wang M, Yu D, Forman BM, Huang W. Farnesoid X receptor antagonizes nuclear factor kappaB in hepatic inflammatory response. Hepatology 48: 1632‐1643, 2008.
 300.Watanabe M, Houten SM, Wang L, Moschetta A, Mangelsdorf DJ, Heyman RA, Moore DD, Auwerx J. Bile acids lower triglyceride levels via a pathway involving FXR, SHP, and SREBP‐1c. J Clin Invest 113: 1408‐1418, 2004.
 301.Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab 291: E275‐E281, 2006.
 302.Westerbacka J, Kolak M, Kiviluoto T, Arkkila P, Siren J, Hamsten A, Fisher RM, Yki‐Jarvinen H. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin‐resistant subjects. Diabetes 56: 2759‐2765, 2007.
 303.Westergaard H, Dietschy JM. The mechanism whereby bile acid micelles increase the rate of fatty acid and cholesterol uptake into the intestinal mucosal cell. J Clin Invest 58: 97‐108, 1976.
 304.Wolfrum C, Asilmaz E, Luca E, Friedman JM, Stoffel M. Foxa2 regulates lipid metabolism and ketogenesis in the liver during fasting and in diabetes. Nature 432: 1027‐1032, 2004.
 305.Xiao C, Lewis GF. Regulation of chylomicron production in humans. Biochim Biophys Acta 1821: 736‐746, 2012.
 306.Xu J, Nakamura MT, Cho HP, Clarke SD. Sterol regulatory element binding protein‐1 expression is suppressed by dietary polyunsaturated fatty acids. A mechanism for the coordinate suppression of lipogenic genes by polyunsaturated fats. J Biol Chem 274: 23577‐23583, 1999.
 307.Xu J, Teran‐Garcia M, Park JH, Nakamura MT, Clarke SD. Polyunsaturated fatty acids suppress hepatic sterol regulatory element‐binding protein‐1 expression by accelerating transcript decay. J Biol Chem 276: 9800‐9807, 2001.
 308.Yamashita H, Takenoshita M, Sakurai M, Bruick RK, Henzel WJ, Shillinglaw W, Arnot D, Uyeda K. A glucose‐responsive transcription factor that regulates carbohydrate metabolism in the liver. Proc Natl Acad Sci U S A 98: 9116‐9121, 2001.
 309.Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S, Sugiyama T, Miyagishi M, Hara K, Tsunoda M, Murakami K, Ohteki T, Uchida S, Takekawa S, Waki H, Tsuno NH, Shibata Y, Terauchi Y, Froguel P, Tobe K, Koyasu S, Taira K, Kitamura T, Shimizu T, Nagai R, Kadowaki T. Cloning of adiponectin receptors that mediate antidiabetic metabolic effects. Nature 423: 762‐769, 2003.
 310.Ye J, Li JZ, Liu Y, Li X, Yang T, Ma X, Li Q, Yao Z, Li P. Cideb, an ER‐ and lipid droplet‐associated protein, mediates VLDL lipidation and maturation by interacting with apolipoprotein B. Cell Metab 9: 177‐190, 2009.
 311.Yonezawa T, Kurata R, Kimura M, Inoko H. Which CIDE are you on? Apoptosis and energy metabolism. Mol Biosyst 7: 91‐100, 2011.
 312.Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM. Control of hepatic gluconeogenesis through the transcriptional coactivator PGC‐1. Nature 413: 131‐138, 2001.
 313.Zamora‐Valdes D, Ponciano‐Rodriguez G, Chavez‐Tapia NC, Mendez‐Sanchez N. The endocannabinoid system in chronic liver disease. Ann Hepatol 4: 248‐254, 2005.
 314.Zechner R, Madeo F. Cell biology: Another way to get rid of fat. Nature 458: 1118‐1119, 2009.
 315.Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 116: 607‐614, 2006.
 316.Zhang D, Liu ZX, Choi CS, Tian L, Kibbey R, Dong J, Cline GW, Wood PA, Shulman GI. Mitochondrial dysfunction due to long‐chain Acyl‐CoA dehydrogenase deficiency causes hepatic steatosis and hepatic insulin resistance. Proc Natl Acad Sci U S A 104: 17075‐17080, 2007.
 317.Zhang S, Wang J, Liu Q, Harnish DC. Farnesoid X receptor agonist WAY‐362450 attenuates liver inflammation and fibrosis in murine model of non‐alcoholic steatohepatitis. J Hepatol 51: 380‐388, 2009.
 318.Zhang Y, Castellani LW, Sinal CJ, Gonzalez FJ, Edwards PA. Peroxisome proliferator‐activated receptor‐gamma coactivator 1alpha (PGC‐1alpha) regulates triglyceride metabolism by activation of the nuclear receptor FXR. Genes Dev 18: 157‐169, 2004.
 319.Zhang Y, Lee FY, Barrera G, Lee H, Vales C, Gonzalez FJ, Willson TM, Edwards PA. Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice. Proc Natl Acad Sci U S A 103: 1006‐1011, 2006.
 320.Zhao A, Yu J, Lew JL, Huang L, Wright SD, Cui J. Polyunsaturated fatty acids are FXR ligands and differentially regulate expression of FXR targets. DNA Cell Biol 23: 519‐526, 2004.
 321.Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 134: 556‐567, 2008.
 322.Zhou L, Xu L, Ye J, Li D, Wang W, Li X, Wu L, Wang H, Guan F, Li P. Cidea promotes hepatic steatosis by sensing dietary fatty acids. Hepatology 56: 95‐107, 2012.
 323.Zhou Z, Yon Toh S, Chen Z, Guo K, Ng CP, Ponniah S, Lin SC, Hong W, Li P. Cidea‐deficient mice have lean phenotype and are resistant to obesity. Nat Genet 35: 49‐56, 2003.

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David Q.‐H. Wang, Piero Portincasa, Brent A. Neuschwander‐Tetri. Steatosis in the Liver. Compr Physiol 2013, 3: 1493-1532. doi: 10.1002/cphy.c130001