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Triglyceride Metabolism in the Liver

Michele Alves‐Bezerra, David E. Cohen

10.1002/cphy.c170012

Source: Volume 8, Issue 1, January 2018

Published online: December 2017

Full Article on Wiley Online Library



ABSTRACT

Triglyceride molecules represent the major form of storage and transport of fatty acids within cells and in the plasma. The liver is the central organ for fatty acid metabolism. Fatty acids accrue in liver by hepatocellular uptake from the plasma and by de novo biosynthesis. Fatty acids are eliminated by oxidation within the cell or by secretion into the plasma within triglyceride‐rich very low‐density lipoproteins. Notwithstanding high fluxes through these pathways, under normal circumstances the liver stores only small amounts of fatty acids as triglycerides. In the setting of overnutrition and obesity, hepatic fatty acid metabolism is altered, commonly leading to the accumulation of triglycerides within hepatocytes, and to a clinical condition known as nonalcoholic fatty liver disease (NAFLD). In this review, we describe the current understanding of fatty acid and triglyceride metabolism in the liver and its regulation in health and disease, identifying potential directions for future research. Advances in understanding the molecular mechanisms underlying the hepatic fat accumulation are critical to the development of targeted therapies for NAFLD. © 2018 American Physiological Society. Compr Physiol 8:1‐22, 2018.

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Figure 1. Figure 1. Major sources for hepatic fatty acids. The three major sources for hepatic fatty acids (FAs) are dietary lipids, adipose tissue derived‐FA and de novo‐synthesized FA. After a meal, dietary lipids are hydrolyzed within the intestinal lumen. Upon intestinal uptake, FA are reesterified to form TG molecules, which are packaged into chylomicrons and delivered primarily to muscle and adipose tissue. The remaining TG present in chylomicron remnants is then transported to the liver and processed intracellularly, leading to FA release within hepatocytes. Carbohydrates, particularly glucose, are utilized in hepatic de novo lipogenesis (DNL) for the production of FA. To be metabolized, FAs are activated to form acyl‐CoA molecules, which can undergo oxidation or be incorporated into complex lipids. Locally synthesized TG can be stored in intracellular lipid droplets (LDs) or packed into VLDL and secreted into the plasma. Upon fasting, intracellular TG stores are mobilized from adipocytes and hepatocytes to release FA products. Hepatic DNL may also contribute to form an acyl‐CoA pool available for energy production, undergoing oxidation by mitochondria, or for VLDL‐TG production. In the setting of overnutrition and insulin resistance, hepatic FA levels are increased due to enhanced lipolysis within adipocytes, which leads to increased circulating levels of FA in the bloodstream, and increased hepatic DNL. Excess FA cannot be consumed by oxidative pathways and FA are instead directed toward the synthesis of TG, leading to increased hepatic TG storage and VLDL overproduction. Arrow thickness denotes rates of metabolic activities.
Figure 2. Figure 2. Hepatic fatty acid transport and metabolism. Within the plasma membrane, FA translocase (FAT)/CD36, plasma membrane FA‐binding protein (FABPpm), and Caveolin‐1 mediate the uptake of fatty acids (FAs) that is bound to circulating albumin. Alternatively, hepatic FA can be obtained by the internalization of chylomicron remnants or by de novo lipogenesis. The latter occurs through the activity of three key enzymes: ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS). In the cytosol, FAs are bound to the fatty acid‐binding protein‐1 (FABP1) and sterol carrier protein‐2 (SCP2), which may control their cellular distribution. FA transport proteins (FATP2, 4, and 5) and long‐chain acyl‐CoA synthetases (ACSL1, 3 and 5) mediate the activation of long‐chain FA to acyl‐CoA molecules and their channeling to metabolic pathways. Although associated with mitochondria, ACSL5 may function to promote triglyceride biosynthesis. In the cytosol, acyl‐CoAs are bound to acyl‐CoA‐binding protein (ACBP) or SCP2. Acyl‐CoA thioesterases (ACOT)/thioesterase superfamily members (Them1, 2, and 5) appear to counteract ACSL activity by catalyzing the hydrolysis of acyl‐CoA molecules into FA and CoA. This may provide additional means of controlling the balance between FA and acyl‐CoA within hepatocytes.
Figure 3. Figure 3. Hepatic triglyceride metabolism. Acyl‐CoA molecules can be esterified to glycerol‐3‐phosphate (G3P) by isoforms of glycerol‐3‐phosphate acyltransferase (GPAT). In hepatocytes, the isoforms are predominantly GPATs 1 and 4. The resulting lysophosphatidic acid (LPA) is acylated by acylglycerol‐3‐phosphate acyltransferases (AGPATs) to form phosphatidic acid (PA), which can be dephosphorylated by phosphatidic acid phosphatase (PAP) to form diacylglycerol (DG). Both PA and DG can be directed toward phospholipid (PL) synthesis. Additionally, diacylglycerol acyltransferases (DGATs 1 and 2) synthesize triglyceride (TG) by acylation of DG. (A) Fatty acids (FAs) synthesized de novo are likely to be channeled to VLDL‐TG production through DGAT1 activity. (B) Exogenous FA appear to be directed toward TG synthesis for storage in lipid droplets by the activity of DGAT2. In addition, lipid droplet‐TG can undergo hydrolysis, with FA rerouted into VLDL by DGAT1.
Figure 4. Figure 4. Triglyceride storage and secretion in hepatocytes. Triglyceride (TG) can be synthesized from diacylglycerol (DG) by diacylglycerol acyltransferases (DGAT1 and 2). DGAT1 preferably provides TG to VLDL during lipidation in the lumen of the endoplasmic reticulum. This process is mediated by microsomal triglyceride transfer protein (MTP), which facilitates the association between TG and apoB100. Transmembrane 6 superfamily member 2 (TM6SF2) may also contribute to VLDL lipidation via yet unknown mechanisms. The nascent VLDL particle is then transferred to the Golgi apparatus through the VLDL transfer vesicle (VTV), followed by a second MTP‐mediated lipidation step. VLDL particles are secreted via a vesicle‐mediated mechanism. TG can also be formed by the activity of DGAT2, which mainly contributes to storage in lipid droplets (LDs). LDs are delimitated by proteins and a phosphatidylcholine (PC)‐enriched surfactant monolayer. Among the LD‐associated proteins, perilipins (PLIN2, 3, and 5), and comparative gene identification‐58 (CGI‐58) contribute to LD structure and/or the regulation of LD‐associated enzymes; CTP‐phosphocholine cytidylyltransferase (CCT) and acyl‐CoA synthetase 3 (ACSL3) may be required for the biosynthesis of lipids; DFF45‐like effector (CIDE) proteins, Cidea, Cideb, and Fsp27, and the microsomal fat‐inducing transmembrane protein 2 (FIT2) are required for LD formation, however their specific cellular roles are incompletely understood. Cideb also contributes to VLDL production and secretion via its interaction with Sar1 and Sec24, which are present in VTV.
Figure 5. Figure 5. Lipolysis and fatty acid oxidation in hepatocytes. The initiation of hepatic lipolysis depends on the activation of adipose triglyceride lipase (ATGL) through the binding to the comparative gene identification‐58 (CGI‐58). ATGL catalyzes the hydrolysis of triglyceride (TG), releasing diacylglycerol (DG). This lipid is further hydrolyzed by hormone sensitive lipase (HSL), releasing monoacylglycerol (MG). Monoacylglycerol lipase (MGL) mediates the breakdown of MG into fatty acid (FA) and glycerol. Alternatively, autophagic pathways, such as macroautophagy and chaperone‐mediated autophagy (CMA), promote the hydrolysis of LD. FA can also be generated from acyl‐CoA by the activity of acyl‐CoA thioesterase 13 (ACOT 13; synonym: thioesterase superfamily member 2, Them2). In the mitochondria outer membrane, long‐chain acyl‐CoA synthetase 1 (ACSL1) converts long‐chain FAs to acyl‐CoAs. ACSL1 interacts physically with carnitine palmitoyltransferase 1 (CPT1). It is likely that ACSL1 channels acyl‐CoA to CPT1 to control the availability of substrates for mitochondrial β‐oxidation. Additionally, acyl‐CoAs can be directed to β‐oxidation in the peroxisome, where fatty acyl‐CoA oxidase (AOX) represents a rate‐limiting step, or ω‐oxidation and α‐oxidation in the endoplasmic reticulum, mediated by P450 4A family members. In addition, part of the acyl‐CoA pool can be directed for TG synthesis and VLDL assembly, enabling the transfer of hepatic lipids to other organs.


Figure 1. Major sources for hepatic fatty acids. The three major sources for hepatic fatty acids (FAs) are dietary lipids, adipose tissue derived‐FA and de novo‐synthesized FA. After a meal, dietary lipids are hydrolyzed within the intestinal lumen. Upon intestinal uptake, FA are reesterified to form TG molecules, which are packaged into chylomicrons and delivered primarily to muscle and adipose tissue. The remaining TG present in chylomicron remnants is then transported to the liver and processed intracellularly, leading to FA release within hepatocytes. Carbohydrates, particularly glucose, are utilized in hepatic de novo lipogenesis (DNL) for the production of FA. To be metabolized, FAs are activated to form acyl‐CoA molecules, which can undergo oxidation or be incorporated into complex lipids. Locally synthesized TG can be stored in intracellular lipid droplets (LDs) or packed into VLDL and secreted into the plasma. Upon fasting, intracellular TG stores are mobilized from adipocytes and hepatocytes to release FA products. Hepatic DNL may also contribute to form an acyl‐CoA pool available for energy production, undergoing oxidation by mitochondria, or for VLDL‐TG production. In the setting of overnutrition and insulin resistance, hepatic FA levels are increased due to enhanced lipolysis within adipocytes, which leads to increased circulating levels of FA in the bloodstream, and increased hepatic DNL. Excess FA cannot be consumed by oxidative pathways and FA are instead directed toward the synthesis of TG, leading to increased hepatic TG storage and VLDL overproduction. Arrow thickness denotes rates of metabolic activities.


Figure 2. Hepatic fatty acid transport and metabolism. Within the plasma membrane, FA translocase (FAT)/CD36, plasma membrane FA‐binding protein (FABPpm), and Caveolin‐1 mediate the uptake of fatty acids (FAs) that is bound to circulating albumin. Alternatively, hepatic FA can be obtained by the internalization of chylomicron remnants or by de novo lipogenesis. The latter occurs through the activity of three key enzymes: ATP‐citrate lyase (ACLY), acetyl‐CoA carboxylase (ACC), and fatty acid synthase (FAS). In the cytosol, FAs are bound to the fatty acid‐binding protein‐1 (FABP1) and sterol carrier protein‐2 (SCP2), which may control their cellular distribution. FA transport proteins (FATP2, 4, and 5) and long‐chain acyl‐CoA synthetases (ACSL1, 3 and 5) mediate the activation of long‐chain FA to acyl‐CoA molecules and their channeling to metabolic pathways. Although associated with mitochondria, ACSL5 may function to promote triglyceride biosynthesis. In the cytosol, acyl‐CoAs are bound to acyl‐CoA‐binding protein (ACBP) or SCP2. Acyl‐CoA thioesterases (ACOT)/thioesterase superfamily members (Them1, 2, and 5) appear to counteract ACSL activity by catalyzing the hydrolysis of acyl‐CoA molecules into FA and CoA. This may provide additional means of controlling the balance between FA and acyl‐CoA within hepatocytes.


Figure 3. Hepatic triglyceride metabolism. Acyl‐CoA molecules can be esterified to glycerol‐3‐phosphate (G3P) by isoforms of glycerol‐3‐phosphate acyltransferase (GPAT). In hepatocytes, the isoforms are predominantly GPATs 1 and 4. The resulting lysophosphatidic acid (LPA) is acylated by acylglycerol‐3‐phosphate acyltransferases (AGPATs) to form phosphatidic acid (PA), which can be dephosphorylated by phosphatidic acid phosphatase (PAP) to form diacylglycerol (DG). Both PA and DG can be directed toward phospholipid (PL) synthesis. Additionally, diacylglycerol acyltransferases (DGATs 1 and 2) synthesize triglyceride (TG) by acylation of DG. (A) Fatty acids (FAs) synthesized de novo are likely to be channeled to VLDL‐TG production through DGAT1 activity. (B) Exogenous FA appear to be directed toward TG synthesis for storage in lipid droplets by the activity of DGAT2. In addition, lipid droplet‐TG can undergo hydrolysis, with FA rerouted into VLDL by DGAT1.


Figure 4. Triglyceride storage and secretion in hepatocytes. Triglyceride (TG) can be synthesized from diacylglycerol (DG) by diacylglycerol acyltransferases (DGAT1 and 2). DGAT1 preferably provides TG to VLDL during lipidation in the lumen of the endoplasmic reticulum. This process is mediated by microsomal triglyceride transfer protein (MTP), which facilitates the association between TG and apoB100. Transmembrane 6 superfamily member 2 (TM6SF2) may also contribute to VLDL lipidation via yet unknown mechanisms. The nascent VLDL particle is then transferred to the Golgi apparatus through the VLDL transfer vesicle (VTV), followed by a second MTP‐mediated lipidation step. VLDL particles are secreted via a vesicle‐mediated mechanism. TG can also be formed by the activity of DGAT2, which mainly contributes to storage in lipid droplets (LDs). LDs are delimitated by proteins and a phosphatidylcholine (PC)‐enriched surfactant monolayer. Among the LD‐associated proteins, perilipins (PLIN2, 3, and 5), and comparative gene identification‐58 (CGI‐58) contribute to LD structure and/or the regulation of LD‐associated enzymes; CTP‐phosphocholine cytidylyltransferase (CCT) and acyl‐CoA synthetase 3 (ACSL3) may be required for the biosynthesis of lipids; DFF45‐like effector (CIDE) proteins, Cidea, Cideb, and Fsp27, and the microsomal fat‐inducing transmembrane protein 2 (FIT2) are required for LD formation, however their specific cellular roles are incompletely understood. Cideb also contributes to VLDL production and secretion via its interaction with Sar1 and Sec24, which are present in VTV.


Figure 5. Lipolysis and fatty acid oxidation in hepatocytes. The initiation of hepatic lipolysis depends on the activation of adipose triglyceride lipase (ATGL) through the binding to the comparative gene identification‐58 (CGI‐58). ATGL catalyzes the hydrolysis of triglyceride (TG), releasing diacylglycerol (DG). This lipid is further hydrolyzed by hormone sensitive lipase (HSL), releasing monoacylglycerol (MG). Monoacylglycerol lipase (MGL) mediates the breakdown of MG into fatty acid (FA) and glycerol. Alternatively, autophagic pathways, such as macroautophagy and chaperone‐mediated autophagy (CMA), promote the hydrolysis of LD. FA can also be generated from acyl‐CoA by the activity of acyl‐CoA thioesterase 13 (ACOT 13; synonym: thioesterase superfamily member 2, Them2). In the mitochondria outer membrane, long‐chain acyl‐CoA synthetase 1 (ACSL1) converts long‐chain FAs to acyl‐CoAs. ACSL1 interacts physically with carnitine palmitoyltransferase 1 (CPT1). It is likely that ACSL1 channels acyl‐CoA to CPT1 to control the availability of substrates for mitochondrial β‐oxidation. Additionally, acyl‐CoAs can be directed to β‐oxidation in the peroxisome, where fatty acyl‐CoA oxidase (AOX) represents a rate‐limiting step, or ω‐oxidation and α‐oxidation in the endoplasmic reticulum, mediated by P450 4A family members. In addition, part of the acyl‐CoA pool can be directed for TG synthesis and VLDL assembly, enabling the transfer of hepatic lipids to other organs.
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Teaching Material

M. Alves-Bezerra, D. E. Cohen. Triglyceride Metabolism in the Liver. Compr Physiol. 8: 2018, 1-22.

Didactic Synopsis

Major Teaching Points:

  • A variety of endogenous and exogenous sources provide fatty acids that can be assembled into to triglycerides within the liver in health and disease;
  • Multiple hepatocellular mechanisms regulate fatty acid uptake, synthesis, transport, and oxidation;
  • Triglycerides can be stored within hepatocytes, undergo lipolysis, or be exported into the bloodstream depending upon physiological and pathological conditions;
  • Mitochondria, endoplasmic reticulum, Golgi apparatus, peroxisomes, and lipid droplets are examples of organelles that participate in fatty acid and triglyceride metabolism;
  • The metabolism of fatty acids and triglyceride is regulated by transcriptional and post-transcriptional mechanisms; and
  • Alterations in fatty acid and triglyceride metabolism lead to non-alcoholic fatty liver disease (NAFLD), which is a common consequence of overnutrition.

Didactic Legends

The figures—in a freely downloadable PowerPoint format—can be found on the Images tab along with the formal legends published in the article. The following legends to the same figures are written to be useful for teaching.

Figure 1. Major sources for hepatic lipids. This figure illustrates the origin of the triglyceride (a common form of fat) that is found in the liver in different physiological states. After a meal, the triglycerides obtained from the diet are modified in the intestine and exported to the bloodstream. Muscle and fat tissue can import and process the triglyceride molecules, modifying them according to their specific needs. The liver can also produce its own triglycerides from sugars and amino acids, in a process called de novo lipogenesis (DNL). Within liver cells, the fat is metabolized in order to be stored in structures called lipid droplets (LDs) or to be exported to other organs via the bloodstream in association with particles called lipoproteins (in this case, very low density lipoprotein, VLDL). During fasting, the breakdown of triglyceride storage depots occurs, releasing fatty acids (the main breakdown products of triglycerides into the blood. When it reaches the liver, it can be used to provide energy through a process called fatty acid oxidation, or can be modified to produce VLDL. In the setting gf obesity or diabetes, the breakdown of triglyceride storage depots is stimulated and the synthesis of triglyceride in the liver increases. It results in the accumulation of triglyceride in the liver and increased levels in the blood, both of which are commonly observed in patients with a common condition known as nonalcoholic fatty liver disease.

Figure 2. Hepatic fatty acid transport and metabolism. Teaching points: many proteins are required in the liver for the import, transport and consumption of fatty acids (FA), the main component of triglycerides. Proteins located in the plasma membrane (FAT/CD36, FABPpm, and Caveolin-1) facilitate the transport FA from the bloodstream into the liver cells. FA imported or produced locally are modified by FATP or ACSL proteins to generate another lipid named acyl-CoA. Acyl-CoA is important because it is the form that is metabolized by enzymes within the liver cells. Acyl-CoA molecules can be converted back to FA by the activities of ACOT/Them proteins. In addition, FA and acyl-CoA interact with proteins (FABP, SCP2, and ACBP) that mediate their transport within liver cells.

Figure 3. Hepatic triglyceride metabolism. This figure summarizes the cellular routes by FA are converted into more complex lipid forms, including triglycerides (TG). Mitochondrial proteins and those within the endoplasmic reticulum (GPAT, AGPAT, PAP, and DGAT) mediate a series of enzymatic reactions including addition of FA-derived intermediates and removal of a phosphate group, which culminates in the formation of TG. TG formed from FA that are synthesized within the liver cells are most likely exported to the bloodstream in VLDL for delivery to other organs. On the other hand, TG produced from FA that are delivered to the liver from the blood are destined for storage in the liver. Other enzymes (DGAT1 and DGAT2) may also regulate the differential usage of FAs.

Figure 4. Triglyceride storage and secretion in hepatocytes. This figure provides detailed information about the variety of proteins that contribute to the formation of triglycerides (TG) that are exported from the liver to the bloodstream within VLDL particles. These proteins are located in three organelles: lipid droplet, endoplasmic reticulum and the Golgi apparatus. The TG produced in the liver can be stored in the LD or directed to the endoplasmic reticulum, where it is used to build pre-VLDL particles. VLDL that are fully matured in the Golgi apparatus by a process that depends microsomal triglyceride transfer protein (MTP). After they are fully formed, VLDL particles are secreted to the bloodstream.

Figure 5. Lipolysis and fatty acid oxidation in hepatocytes. Teaching points: triglycerides (TG) stored in the liver can be metabolized to provide energy to the liver cell itself. This process is initiated by enzymes know as lipases (ATGL, HSL, and MGL) and culminates in the release of fatty acid (FA), the main constituent of TG. Autophagy, a lysosome-dependent pathway to recover and recycle cellular constituents, also mediates the breakdown of TG into FA. FA can also be produced from acyl-CoA lipids by enzymes referred to as ACOT/Them. In order to enter cellular metabolic pathways, FA must be converted to acyl-CoA by ACSL enzymes. They can then be used as a fuel when oxidized in the mitochondria, peroxisome, or endoplasmic reticulum, or can be used to build TG that will be exported to the bloodstream in VLDL particles.

 


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Article Title: Triglyceride Metabolism in the Liver
 

How to Cite

Michele Alves‐Bezerra, David E. Cohen. Triglyceride Metabolism in the Liver. Compr Physiol 2017, 8: 1-22. doi: 10.1002/cphy.c170012