Comprehensive Physiology Wiley Online Library

Energy Metabolism in the Liver

Full Article on Wiley Online Library


The liver is an essential metabolic organ, and its metabolic function is controlled by insulin and other metabolic hormones. Glucose is converted into pyruvate through glycolysis in the cytoplasm, and pyruvate is subsequently oxidized in the mitochondria to generate ATP through the TCA cycle and oxidative phosphorylation. In the fed state, glycolytic products are used to synthesize fatty acids through de novo lipogenesis. Long‐chain fatty acids are incorporated into triacylglycerol, phospholipids, and/or cholesterol esters in hepatocytes. These complex lipids are stored in lipid droplets and membrane structures, or secreted into the circulation as very low‐density lipoprotein particles. In the fasted state, the liver secretes glucose through both glycogenolysis and gluconeogenesis. During pronged fasting, hepatic gluconeogenesis is the primary source for endogenous glucose production. Fasting also promotes lipolysis in adipose tissue, resulting in release of nonesterified fatty acids which are converted into ketone bodies in hepatic mitochondria though β‐oxidation and ketogenesis. Ketone bodies provide a metabolic fuel for extrahepatic tissues. Liver energy metabolism is tightly regulated by neuronal and hormonal signals. The sympathetic system stimulates, whereas the parasympathetic system suppresses, hepatic gluconeogenesis. Insulin stimulates glycolysis and lipogenesis but suppresses gluconeogenesis, and glucagon counteracts insulin action. Numerous transcription factors and coactivators, including CREB, FOXO1, ChREBP, SREBP, PGC‐1α, and CRTC2, control the expression of the enzymes which catalyze key steps of metabolic pathways, thus controlling liver energy metabolism. Aberrant energy metabolism in the liver promotes insulin resistance, diabetes, and nonalcoholic fatty liver diseases. © 2014 American Physiological Society. Compr Physiol 4:177‐197, 2014.

Comprehensive Physiology offers downloadable PowerPoint presentations of figures for non-profit, educational use, provided the content is not modified and full credit is given to the author and publication.

Download a PowerPoint presentation of all images

Figure 1. Figure 1. Glucose metabolic pathways. The gluconeogenic pathways are marked in blue, and the pentose phosphate pathways are marked in orange. GCK: glucokinase; G6Pase: glucose‐6‐phosphatase; G6P: glucose 1‐phosphate; G1P: glucose 1‐phosphate; GP: glycogen phosphorylase; GS: glycogen synthase; PFK: 6‐phosphofructo‐1 kinase; FBPase: fructose 1,6 bisphosphatase; F‐1,6‐P:; GAP: glyceraldehyde 3‐phosphate; DHAP: dihydroxyacetone phosphate; L‐PK: liver pyruvate kinase; PC: pyruvate carboxylase; PDC: pyruvate dehydrogenase complex; and PDKs: pyruvate dehydrogenase kinases.
Figure 2. Figure 2. Regulation of liver glucose and fatty acid metabolism by insulin and glucagon.
Figure 3. Figure 3. Lipogenic pathways. Lipogenic enzymes are marked in blue. ACL: ATP‐citrate lyase; ACC: acetyl‐CoA carboxylase; FAS: fatty acid synthase; Elovls: fatty acyl‐CoA elongases; SCDs: stearoyl‐CoA desaturases; and TAG: triacylglycerol.

Figure 1. Glucose metabolic pathways. The gluconeogenic pathways are marked in blue, and the pentose phosphate pathways are marked in orange. GCK: glucokinase; G6Pase: glucose‐6‐phosphatase; G6P: glucose 1‐phosphate; G1P: glucose 1‐phosphate; GP: glycogen phosphorylase; GS: glycogen synthase; PFK: 6‐phosphofructo‐1 kinase; FBPase: fructose 1,6 bisphosphatase; F‐1,6‐P:; GAP: glyceraldehyde 3‐phosphate; DHAP: dihydroxyacetone phosphate; L‐PK: liver pyruvate kinase; PC: pyruvate carboxylase; PDC: pyruvate dehydrogenase complex; and PDKs: pyruvate dehydrogenase kinases.

Figure 2. Regulation of liver glucose and fatty acid metabolism by insulin and glucagon.

Figure 3. Lipogenic pathways. Lipogenic enzymes are marked in blue. ACL: ATP‐citrate lyase; ACC: acetyl‐CoA carboxylase; FAS: fatty acid synthase; Elovls: fatty acyl‐CoA elongases; SCDs: stearoyl‐CoA desaturases; and TAG: triacylglycerol.
 1.Abu‐Elheiga L, Brinkley WR, Zhong L, Chirala SS, Woldegiorgis G, Wakil SJ. The subcellular localization of acetyl‐CoA carboxylase 2. Proc Natl Acad Sci U S A 97: 1444‐1449, 2000.
 2.Abu‐Elheiga L, Matzuk MM, Abo‐Hashema KA, Wakil SJ. Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl‐CoA carboxylase 2. Science 291: 2613‐2616, 2001.
 3.Abu‐Elheiga L, Matzuk MM, Kordari P, Oh W, Shaikenov T, Gu Z, Wakil SJ. Mutant mice lacking acetyl‐CoA carboxylase 1 are embryonically lethal. Proc Natl Acad Sci U S A 102: 12011‐12016, 2005.
 4.Agius L. Glucokinase and molecular aspects of liver glycogen metabolism. Biochem J 414: 1‐18, 2008.
 5.Andreelli F, Foretz M, Knauf C, Cani PD, Perrin C, Iglesias MA, Pillot B, Bado A, Tronche F, Mithieux G, Vaulont S, Burcelin R, Viollet B. Liver adenosine monophosphate‐activated kinase‐alpha2 catalytic subunit is a key target for the control of hepatic glucose production by adiponectin and leptin but not insulin. Endocrinology 147: 2432‐2441, 2006.
 6.Arafat AM, Kaczmarek P, Skrzypski M, Pruszynska‐Oszmalek E, Kolodziejski P, Szczepankiewicz D, Sassek M, Wojciechowicz T, Wiedenmann B, Pfeiffer AF, Nowak KW, Strowski MZ. Glucagon increases circulating fibroblast growth factor 21 independently of endogenous insulin levels: a novel mechanism of glucagon‐stimulated lipolysis? Diabetologia 56: 588‐597, 2013.
 7.Arden C, Tudhope SJ, Petrie JL, Al‐Oanzi ZH, Cullen KS, Lange AJ, Towle HC, Agius L. Fructose 2,6‐bisphosphate is essential for glucose‐regulated gene transcription of glucose‐6‐phosphatase and other ChREBP target genes in hepatocytes. Biochem J 443: 111‐123, 2012.
 8.Arkan MC, Hevener AL, Greten FR, Maeda S, Li ZW, Long JM, Wynshaw‐Boris A, Poli G, Olefsky J, Karin M. IKK‐beta links inflammation to obesity‐induced insulin resistance. Nat Med 11: 191‐198, 2005.
 9.Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos‐Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 5: 426‐437, 2007.
 10.Baffy G. Kupffer cells in non‐alcoholic fatty liver disease: The emerging view. J Hepatol 51: 212‐223, 2009.
 11.Bedford DC, Kasper LH, Wang R, Chang Y, Green DR, Brindle PK. Disrupting the CH1 domain structure in the acetyltransferases CBP and p300 results in lean mice with increased metabolic control. Cell Metab 14: 219‐230, 2011.
 12.Bellafante E, Murzilli S, Salvatore L, Latorre D, Villani G, Moschetta A. Hepatic‐specific activation of peroxisome proliferator‐activated receptor gamma coactivator‐1beta protects against steatohepatitis. Hepatology 57: 1343‐1356, 2013.
 13.Benhamed F, Denechaud PD, Lemoine M, Robichon C, Moldes M, Bertrand‐Michel J, Ratziu V, Serfaty L, Housset C, Capeau J, Girard J, Guillou H, Postic C. The lipogenic transcription factor ChREBP dissociates hepatic steatosis from insulin resistance in mice and humans. J Clin Invest 122: 2176‐2194, 2012.
 14.Berglund ED, Lustig DG, Baheza RA, Hasenour CM, Lee‐Young RS, Donahue EP, Lynes SE, Swift LL, Charron MJ, Damon BM, Wasserman DH. Hepatic glucagon action is essential for exercise‐induced reversal of mouse fatty liver. Diabetes 60: 2720‐2729, 2011.
 15.Berglund ED, Vianna CR, Donato J, Jr., Kim MH, Chuang JC, Lee CE, Lauzon DA, Lin P, Brule LJ, Scott MM, Coppari R, Elmquist JK. Direct leptin action on POMC neurons regulates glucose homeostasis and hepatic insulin sensitivity in mice. J Clin Invest 122: 1000‐1009, 2012.
 16.Bhatnagar S, Damron HA, Hillgartner FB. Fibroblast growth factor‐19, a novel factor that inhibits hepatic fatty acid synthesis. J Biol Chem 284: 10023‐10033, 2009.
 17.Bricambert J, Miranda J, Benhamed F, Girard J, Postic C, Dentin R. Salt‐inducible kinase 2 links transcriptional coactivator p300 phosphorylation to the prevention of ChREBP‐dependent hepatic steatosis in mice. J Clin Invest 120: 4316‐4331, 2010.
 18.Bu SY, Mashek DG. Hepatic long‐chain acyl‐CoA synthetase 5 mediates fatty acid channeling between anabolic and catabolic pathways. J Lipid Res 51: 3270‐3280, 2010.
 19.Buettner C, Pocai A, Muse ED, Etgen AM, Myers MG, Jr., Rossetti L. Critical role of STAT3 in leptin's metabolic actions. Cell Metab 4: 49‐60, 2006.
 20.Bugge A, Feng D, Everett LJ, Briggs ER, Mullican SE, Wang F, Jager J, Lazar MA. Rev‐erbalpha and Rev‐erbbeta coordinately protect the circadian clock and normal metabolic function. Genes Dev 26: 657‐667, 2012.
 21.Burgess SC, Hausler N, Merritt M, Jeffrey FM, Storey C, Milde A, Koshy S, Lindner J, Magnuson MA, Malloy CR, Sherry AD. Impaired tricarboxylic acid cycle activity in mouse livers lacking cytosolic phosphoenolpyruvate carboxykinase. J Biol Chem 279: 48941‐48949, 2004.
 22.Cai D, Yuan M, Frantz DF, Melendez PA, Hansen L, Lee J, Shoelson SE. Local and systemic insulin resistance resulting from hepatic activation of IKK‐beta and NF‐kappaB. Nat Med 11: 183‐190, 2005.
 23.Calkin AC, Tontonoz P. Transcriptional integration of metabolism by the nuclear sterol‐activated receptors LXR and FXR. Nat Rev Mol Cell Biol 13: 213‐224, 2012.
 24.Cao H, Gerhold K, Mayers JR, Wiest MM, Watkins SM, Hotamisligil GS. Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism. Cell 134: 933‐944, 2008.
 25.Cao H, Sekiya M, Ertunc ME, Burak MF, Mayers JR, White A, Inouye K, Rickey LM, Ercal BC, Furuhashi M, Tuncman G, Hotamisligil GS. Adipocyte lipid chaperone AP2 is a secreted adipokine regulating hepatic glucose production. Cell Metab 17: 768‐778, 2013.
 26.Cao W, Collins QF, Becker TC, Robidoux J, Lupo EG, Jr., Xiong Y, Daniel KW, Floering L, Collins S. p38 Mitogen‐activated protein kinase plays a stimulatory role in hepatic gluconeogenesis. J Biol Chem 280: 42731‐42737, 2005.
 27.Caron S, Samanez CH, Dehondt H, Ploton M, Briand O, Lien F, Dorchies E, Dumont J, Postic C, Cariou B, Lefebvre P, Staels B. The farnesoid X receptor inhibits the transcriptional activity of the carbohydrate response element binding protein in human hepatocytes – R2. Mol Cell Biol 33: 2202‐2211, 2013.
 28.Casado M, Vallet VS, Kahn A, Vaulont S. Essential role in vivo of upstream stimulatory factors for a normal dietary response of the fatty acid synthase gene in the liver. J Biol Chem 274: 2009‐2013, 1999.
 29.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.
 30.Chakravarthy MV, Lodhi IJ, Yin L, Malapaka RR, Xu HE, Turk J, Semenkovich CF. Identification of a physiologically relevant endogenous ligand for PPARalpha in liver. Cell 138: 476‐488, 2009.
 31.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.
 32.Chen D, Bruno J, Easlon E, Lin SJ, Cheng HL, Alt FW, Guarente L. Tissue‐specific regulation of SIRT1 by calorie restriction. Genes Dev 22: 1753‐1757, 2008.
 33.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.
 34.Chen M, Gavrilova O, Zhao WQ, Nguyen A, Lorenzo J, Shen L, Nackers L, Pack S, Jou W, Weinstein LS. Increased glucose tolerance and reduced adiposity in the absence of fasting hypoglycemia in mice with liver‐specific Gs alpha deficiency. J Clin Invest 115: 3217‐3227, 2005.
 35.Chen W, Chen G, Head DL, Mangelsdorf DJ, Russell DW. Enzymatic reduction of oxysterols impairs LXR signaling in cultured cells and the livers of mice. Cell Metab 5: 73‐79, 2007.
 36.Chen Z, Sheng L, Shen H, Zhao Y, Wang S, Brink R, Rui L. Hepatic TRAF2 regulates glucose metabolism through enhancing glucagon responses. Diabetes 61: 566‐573, 2012.
 37.Cheung GW, Kokorovic A, Lam CK, Chari M, Lam TK. Intestinal cholecystokinin controls glucose production through a neuronal network. Cell Metab 10: 99‐109, 2009.
 38.Chopra AR, Louet JF, Saha P, An J, Demayo F, Xu J, York B, Karpen S, Finegold M, Moore D, Chan L, Newgard CB, O'Malley BW. Absence of the SRC‐2 coactivator results in a glycogenopathy resembling Von Gierke's disease. Science 322: 1395‐1399, 2008.
 39.Cohen P, Miyazaki M, Socci ND, Hagge‐Greenberg A, Liedtke W, Soukas AA, Sharma R, Hudgins LC, Ntambi JM, Friedman JM. Role for stearoyl‐CoA desaturase‐1 in leptin‐mediated weight loss. Science 297: 240‐243, 2002.
 40.Conarello SL, Jiang G, Mu J, Li Z, Woods J, Zycband E, Ronan J, Liu F, Roy RS, Zhu L, Charron MJ, Zhang BB. Glucagon receptor knockout mice are resistant to diet‐induced obesity and streptozotocin‐mediated beta cell loss and hyperglycaemia. Diabetologia 50: 142‐150, 2007.
 41.Consoli A, Nurjhan N, Capani F, Gerich J. Predominant role of gluconeogenesis in increased hepatic glucose production in NIDDM. Diabetes 38: 550‐557, 1989.
 42.Cui Y, Hosui A, Sun R, Shen K, Gavrilova O, Chen W, Cam MC, Gao B, Robinson GW, Hennighausen L. Loss of signal transducer and activator of transcription 5 leads to hepatosteatosis and impaired liver regeneration. Hepatology 46: 504‐513, 2007.
 43.DeAngelis AM, Heinrich G, Dai T, Bowman TA, Patel PR, Lee SJ, Hong EG, Jung DY, Assmann A, Kulkarni RN, Kim JK, Najjar SM. Carcinoembryonic antigen‐related cell adhesion molecule 1: A link between insulin and lipid metabolism. Diabetes 57: 2296‐2303, 2008.
 44.Delibegovic M, Zimmer D, Kauffman C, Rak K, Hong EG, Cho YR, Kim JK, Kahn BB, Neel BG, Bence KK. Liver‐specific deletion of protein‐tyrosine phosphatase 1B (PTP1B) improves metabolic syndrome and attenuates diet‐induced endoplasmic reticulum stress. Diabetes 58: 590‐599, 2009.
 45.Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J, Postic C. ChREBP, but not LXRs, is required for the induction of glucose‐regulated genes in mouse liver. J Clin Invest 118: 956‐964, 2008.
 46.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.
 47.Dentin R, Liu Y, Koo SH, Hedrick S, Vargas T, Heredia J, Yates J, 3rd, Montminy M. Insulin modulates gluconeogenesis by inhibition of the coactivator TORC2. Nature 449: 366‐369, 2007.
 48.Dentin R, Tomas‐Cobos L, Foufelle F, Leopold J, Girard J, Postic C, Ferre P. Glucose 6‐phosphate, rather than xylulose 5‐phosphate, is required for the activation of ChREBP in response to glucose in the liver. J Hepatol 56: 199‐209, 2012.
 49.Doege H, Baillie RA, Ortegon AM, Tsang B, Wu Q, Punreddy S, Hirsch D, Watson N, Gimeno RE, Stahl A. Targeted deletion of FATP5 reveals multiple functions in liver metabolism: Alterations in hepatic lipid homeostasis. Gastroenterology 130: 1245‐1258, 2006.
 50.Dong X, Park S, Lin X, Copps K, Yi X, White MF. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. J Clin Invest 116: 101‐114, 2006.
 51.Dong XC, Copps KD, Guo S, Li Y, Kollipara R, DePinho RA, White MF. Inactivation of hepatic Foxo1 by insulin signaling is required for adaptive nutrient homeostasis and endocrine growth regulation. Cell Metab 8: 65‐76, 2008.
 52.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.
 53.Duan C, Li M, Rui L. SH2‐B promotes insulin receptor substrate 1 (IRS1)‐ and IRS2‐mediated activation of the phosphatidylinositol 3‐kinase pathway in response to leptin. J Biol Chem 279: 43684‐43691, 2004.
 54.Duan C, Yang H, White MF, Rui L. Disruption of the SH2‐B gene causes age‐dependent insulin resistance and glucose intolerance. Mol Cell Biol 24: 7435‐7443, 2004.
 55.Duckworth WC, Bennett RG, Hamel FG. Insulin degradation: Progress and potential. Endocr Rev 19: 608‐624, 1998.
 56.Erion DM, Ignatova ID, Yonemitsu S, Nagai Y, Chatterjee P, Weismann D, Hsiao JJ, Zhang D, Iwasaki T, Stark R, Flannery C, Kahn M, Carmean CM, Yu XX, Murray SF, Bhanot S, Monia BP, Cline GW, Samuel VT, Shulman GI. Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element‐binding protein. Cell Metab 10: 499‐506, 2009.
 57.Erion DM, Yonemitsu S, Nie Y, Nagai Y, Gillum MP, Hsiao JJ, Iwasaki T, Stark R, Weismann D, Yu XX, Murray SF, Bhanot S, Monia BP, Horvath TL, Gao Q, Samuel VT, Shulman GI. SirT1 knockdown in liver decreases basal hepatic glucose production and increases hepatic insulin responsiveness in diabetic rats. Proc Natl Acad Sci U S A 106: 11288‐11293, 2009.
 58.Escande C, Chini CC, Nin V, Dykhouse KM, Novak CM, Levine J, van Deursen J, Gores GJ, Chen J, Lou Z, Chini EN. Deleted in breast cancer‐1 regulates SIRT1 activity and contributes to high‐fat diet‐induced liver steatosis in mice. J Clin Invest 120: 545‐558, 2010.
 59.Fafalios A, Ma J, Tan X, Stoops J, Luo J, Defrances MC, Zarnegar R. A hepatocyte growth factor receptor (Met)‐insulin receptor hybrid governs hepatic glucose metabolism. Nat Med 17: 1577‐1584, 2011.
 60.Falcon A, Doege H, Fluitt A, Tsang B, Watson N, Kay MA, Stahl A. FATP2 is a hepatic fatty acid transporter and peroxisomal very long‐chain acyl‐CoA synthetase. Am J Physiol Endocrinol Metab 299: E384‐393, 2010.
 61.Fan CY, Pan J, Chu R, Lee D, Kluckman KD, Usuda N, Singh I, Yeldandi AV, Rao MS, Maeda N, Reddy JK. Hepatocellular and hepatic peroxisomal alterations in mice with a disrupted peroxisomal fatty acyl‐coenzyme A oxidase gene. J Biol Chem 271: 24698‐24710, 1996.
 62.Fan Y, Menon RK, Cohen P, Hwang D, Clemens T, DiGirolamo DJ, Kopchick JJ, Le Roith D, Trucco M, Sperling MA. Liver‐specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem 284: 19937‐19944, 2009.
 63.Feng D, Liu T, Sun Z, Bugge A, Mullican SE, Alenghat T, Liu XS, Lazar MA. A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism. Science 331: 1315‐1319, 2011.
 64.Finck BN, Gropler MC, Chen Z, Leone TC, Croce MA, Harris TE, Lawrence JC, Jr., Kelly DP. Lipin 1 is an inducible amplifier of the hepatic PGC‐1alpha/PPARalpha regulatory pathway. Cell Metab 4: 199‐210, 2006.
 65.Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, Nicol CJ, Vinson C, Gonzalez FJ, Reitman ML. Liver peroxisome proliferator‐activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 278: 34268‐34276, 2003.
 66.Gelling RW, Du XQ, Dichmann DS, Romer J, Huang H, Cui L, Obici S, Tang B, Holst JJ, Fledelius C, Johansen PB, Rossetti L, Jelicks LA, Serup P, Nishimura E, Charron MJ. Lower blood glucose, hyperglucagonemia, and pancreatic alpha cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100: 1438‐1443, 2003.
 67.Granneman JG, Moore HP, Krishnamoorthy R, Rathod M. Perilipin controls lipolysis by regulating the interactions of AB‐hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). J Biol Chem 284: 34538‐34544, 2009.
 68.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.
 69.Guinez C, Filhoulaud G, Rayah‐Benhamed F, Marmier S, Dubuquoy C, Dentin R, Moldes M, Burnol AF, Yang X, Lefebvre T, Girard J, Postic C. O‐GlcNAcylation increases ChREBP protein content and transcriptional activity in the liver. Diabetes 60: 1399‐1413, 2011.
 70.Guo S, Copps KD, Dong X, Park S, Cheng Z, Pocai A, Rossetti L, Sajan M, Farese RV, White MF. The Irs1 branch of the insulin signaling cascade plays a dominant role in hepatic nutrient homeostasis. Mol Cell Biol 29: 5070‐5083, 2009.
 71.Guo S, Rena G, Cichy S, He X, Cohen P, Unterman T. Phosphorylation of serine 256 by protein kinase B disrupts transactivation by FKHR and mediates effects of insulin on insulin‐like growth factor‐binding protein‐1 promoter activity through a conserved insulin response sequence. J Biol Chem 274: 17184‐17192, 1999.
 72.Habegger KM, Stemmer K, Cheng C, Muller TD, Heppner KM, Ottaway N, Holland J, Hembree JL, Smiley D, Gelfanov V, Krishna R, Arafat AM, Konkar A, Belli S, Kapps M, Woods SC, Hofmann SM, D'Alessio D, Pfluger PT, Perez‐Tilve D, Seeley RJ, Konishi M, Itoh N, Kharitonenkov A, Spranger J, Dimarchi RD, Tschop MH. Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes 62: 1453‐1463, 2013.
 73.Haeusler RA, Kaestner KH, Accili D. FoxOs function synergistically to promote glucose production. J Biol Chem 285: 35245‐35248, 2010.
 74.Hagiwara A, Cornu M, Cybulski N, Polak P, Betz C, Trapani F, Terracciano L, Heim MH, Ruegg MA, Hall MN. Hepatic mTORC2 activates glycolysis and lipogenesis through Akt, glucokinase, and SREBP1c. Cell Metab 15: 725‐738, 2012.
 75.Hallows WC, Yu W, Smith BC, Devries MK, Ellinger JJ, Someya S, Shortreed MR, Prolla T, Markley JL, Smith LM, Zhao S, Guan KL, Denu JM. Sirt3 promotes the urea cycle and fatty acid oxidation during dietary restriction. Molecular cell 41: 139‐149, 2011.
 76.Hancock AS, Du A, Liu J, Miller M, May CL. Glucagon deficiency reduces hepatic glucose production and improves glucose tolerance in adult mice. Mol Endocrinol 24: 1605‐1614, 2010.
 77.Harada N, Oda Z, Hara Y, Fujinami K, Okawa M, Ohbuchi K, Yonemoto M, Ikeda Y, Ohwaki K, Aragane K, Tamai Y, Kusunoki J. Hepatic de novo lipogenesis is present in liver‐specific ACC1‐deficient mice. Mol Cell Biol 27: 1881‐1888, 2007.
 78.He L, Sabet A, Djedjos S, Miller R, Sun XJ, Hussain MA, Radovick S, Wondisford FE. Metformin and insulin suppress hepatic gluconeogenesis through phosphorylation of CREB binding protein. Cell 137: 635‐646, 2009.
 79.Henao‐Mejia J, Elinav E, Jin C, Hao L, Mehal WZ, Strowig T, Thaiss CA, Kau AL, Eisenbarth SC, Jurczak MJ, Camporez JP, Shulman GI, Gordon JI, Hoffman HM, Flavell RA. Inflammasome‐mediated dysbiosis regulates progression of NAFLD and obesity. Nature 482: 179‐185, 2012.
 80.Herzig S, Hedrick S, Morantte I, Koo SH, Galimi F, Montminy M. CREB controls hepatic lipid metabolism through nuclear hormone receptor PPAR‐gamma. Nature 426: 190‐193, 2003.
 81.Herzig S, Long F, Jhala US, Hedrick S, Quinn R, Bauer A, Rudolph D, Schutz G, Yoon C, Puigserver P, Spiegelman B, Montminy M. CREB regulates hepatic gluconeogenesis through the coactivator PGC‐1. Nature 413: 179‐183, 2001.
 82.Hirschey MD, Shimazu T, Goetzman E, Jing E, Schwer B, Lombard DB, Grueter CA, Harris C, Biddinger S, Ilkayeva OR, Stevens RD, Li Y, Saha AK, Ruderman NB, Bain JR, Newgard CB, Farese RV, Jr., Alt FW, Kahn CR, Verdin E. SIRT3 regulates mitochondrial fatty‐acid oxidation by reversible enzyme deacetylation. Nature 464: 121‐125, 2010.
 83.Holland WL, Adams AC, Brozinick JT, Bui HH, Miyauchi Y, Kusminski CM, Bauer SM, Wade M, Singhal E, Cheng CC, Volk K, Kuo MS, Gordillo R, Kharitonenkov A, Scherer PE. An FGF21‐adiponectin‐ceramide axis controls energy expenditure and insulin action in mice. Cell Metab 17: 790‐797, 2013.
 84.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.
 85.Hotamisligil GS. Inflammation and metabolic disorders. Nature 444: 860‐867, 2006.
 86.Huang J, Jia Y, Fu T, Viswakarma N, Bai L, Rao MS, Zhu Y, Borensztajn J, Reddy JK. Sustained activation of PPARalpha by endogenous ligands increases hepatic fatty acid oxidation and prevents obesity in ob/ob mice. FASEB J 26: 628‐638, 2012.
 87.Huang W, Metlakunta A, Dedousis N, Zhang P, Sipula I, Dube JJ, Scott DK, O'Doherty RM. Depletion of liver Kupffer cells prevents the development of diet‐induced hepatic steatosis and insulin resistance. Diabetes 59: 347‐357, 2010.
 88.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.
 89.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: E358‐364, 2006.
 90.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.
 91.Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, Li Y, Goetz R, Mohammadi M, Esser V, Elmquist JK, Gerard RD, Burgess SC, Hammer RE, Mangelsdorf DJ, Kliewer SA. Endocrine regulation of the fasting response by PPARalpha‐mediated induction of fibroblast growth factor 21. Cell Metab 5: 415‐425, 2007.
 92.Inagaki T, Lin VY, Goetz R, Mohammadi M, Mangelsdorf DJ, Kliewer SA. Inhibition of growth hormone signaling by the fasting‐induced hormone FGF21. Cell Metab 8: 77‐83, 2008.
 93.Inoue H, Ogawa W, Asakawa A, Okamoto Y, Nishizawa A, Matsumoto M, Teshigawara K, Matsuki Y, Watanabe E, Hiramatsu R. Role of hepatic STAT3 in brain‐insulin action on hepatic glucose production. Cell Metabolism 3: 267‐275, 2006.
 94.Inoue H, Ogawa W, Ozaki M, Haga S, Matsumoto M, Furukawa K, Hashimoto N, Kido Y, Mori T, Sakaue H, Teshigawara K, Jin S, Iguchi H, Hiramatsu R, LeRoith D, Takeda K, Akira S, Kasuga M. Role of STAT‐3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo. Nat Med 10: 168‐174, 2004.
 95.Inoue Y, Inoue J, Lambert G, Yim SH, Gonzalez FJ. Disruption of hepatic C/EBPalpha results in impaired glucose tolerance and age‐dependent hepatosteatosis. J Biol Chem 279: 44740‐44748, 2004.
 96.Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B. SIN1/MIP1 maintains rictor‐mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127: 125‐137, 2006.
 97.Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature 383: 728‐731, 1996.
 98.Jelen S, Gena P, Lebeck J, Rojek A, Praetorius J, Frokiaer J, Fenton RA, Nielsen S, Calamita G, Rutzler M. Aquaporin‐9 and urea transporter‐A gene deletions affect urea transmembrane passage in murine hepatocytes. Am J Physiol Gastrointest Liver Physiol 303: G1279‐G1287, 2012.
 99.Jeong JY, Jeoung NH, Park KG, Lee IK. Transcriptional regulation of pyruvate dehydrogenase kinase. Diabetes Metab J 36: 328‐335, 2012.
 100.Jeoung NH, Harris RA. Pyruvate dehydrogenase kinase‐4 deficiency lowers blood glucose and improves glucose tolerance in diet‐induced obese mice. Am J Physiol Endocrinol Metab 295: E46‐54, 2008.
 101.Jeoung NH, Wu P, Joshi MA, Jaskiewicz J, Bock CB, Depaoli‐Roach AA, Harris RA. Role of pyruvate dehydrogenase kinase isoenzyme 4 (PDHK4) in glucose homoeostasis during starvation. Biochem J 397: 417‐425, 2006.
 102.Jiang G, Zhang BB. Glucagon and regulation of glucose metabolism. Am J Physiol Endocrinol Metab 284: E671‐678, 2003.
 103.Jiang W, Wang S, Xiao M, Lin Y, Zhou L, Lei Q, Xiong Y, Guan KL, Zhao S. Acetylation regulates gluconeogenesis by promoting PEPCK1 degradation via recruiting the UBR5 ubiquitin ligase. Molecular cell 43: 33‐44, 2011.
 104.Jornayvaz FR, Shulman GI. Diacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistance. Cell Metab 15: 574‐584, 2012.
 105.Kabashima T, Kawaguchi T, Wadzinski BE, Uyeda K. Xylulose 5‐phosphate mediates glucose‐induced lipogenesis by xylulose 5‐phosphate‐activated protein phosphatase in rat liver. Proc Natl Acad Sci U S A 100: 5107‐5112, 2003.
 106.Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferre P, Foufelle F. GRP78 expression inhibits insulin and ER stress‐induced SREBP‐1c activation and reduces hepatic steatosis in mice. J Clin Invest 119: 1201‐1215, 2009.
 107.Kaufman RJ, Back SH, Song B, Han J, Hassler J. The unfolded protein response is required to maintain the integrity of the endoplasmic reticulum, prevent oxidative stress and preserve differentiation in beta‐cells. Diabetes Obes Metab 12(Suppl 2): 99‐107, 2010.
 108.Kawaguchi T, Takenoshita M, Kabashima T, Uyeda K. Glucose and cAMP regulate the L‐type pyruvate kinase gene by phosphorylation/dephosphorylation of the carbohydrate response element binding protein. Proc Natl Acad Sci U S A 98: 13710‐13715, 2001.
 109.Kemper JK, Xiao Z, Ponugoti B, Miao J, Fang S, Kanamaluru D, Tsang S, Wu SY, Chiang CM, Veenstra TD. FXR acetylation is normally dynamically regulated by p300 and SIRT1 but constitutively elevated in metabolic disease states. Cell Metab 10: 392‐404, 2009.
 110.Kersten S, Seydoux J, Peters JM, Gonzalez FJ, Desvergne B, Wahli W. Peroxisome proliferator‐activated receptor alpha mediates the adaptive response to fasting. J Clin Invest 103: 1489‐1498, 1999.
 111.Kim DH, Perdomo G, Zhang T, Slusher S, Lee S, Phillips BE, Fan Y, Giannoukakis N, Gramignoli R, Strom S, Ringquist S, Dong HH. FoxO6 integrates insulin signaling with gluconeogenesis in the liver. Diabetes 60: 2763‐2774, 2011.
 112.Kim HS, Xiao C, Wang RH, Lahusen T, Xu X, Vassilopoulos A, Vazquez‐Ortiz G, Jeong WI, Park O, Ki SH, Gao B, Deng CX. Hepatic‐specific disruption of SIRT6 in mice results in fatty liver formation due to enhanced glycolysis and triglyceride synthesis. Cell Metab 12: 224‐236, 2010.
 113.Kim JE, Chen J, Lou Z. DBC1 is a negative regulator of SIRT1. Nature 451: 583‐586, 2008.
 114.Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez‐Carrasco W, Goldberg IJ, Breslow JL, Shulman GI. Tissue‐specific overexpression of lipoprotein lipase causes tissue‐specific insulin resistance. Proc Natl Acad Sci U S A 98: 7522‐7527, 2001.
 115.Kim YD, Kim YH, Tadi S, Yu JH, Yim YH, Jeoung NH, Shong M, Hennighausen L, Harris RA, Lee IK, Lee CH, Choi HS. Metformin inhibits growth hormone‐mediated hepatic PDK4 gene expression through induction of orphan nuclear receptor small heterodimer partner. Diabetes 61: 2484‐2494, 2012.
 116.Kim YD, Li T, Ahn SW, Kim DK, Lee JM, Hwang SL, Kim YH, Lee CH, Lee IK, Chiang JY, Choi HS. Orphan nuclear receptor small heterodimer partner negatively regulates growth hormone‐mediated induction of hepatic gluconeogenesis through inhibition of signal transducer and activator of transcription 5 (STAT5) transactivation. J Biol Chem 287: 37098‐37108, 2012.
 117.Kimura T, Christoffels VM, Chowdhury S, Iwase K, Matsuzaki H, Mori M, Lamers WH, Darlington GJ, Takiguchi M. Hypoglycemia‐associated hyperammonemia caused by impaired expression of ornithine cycle enzyme genes in C/EBPalpha knockout mice. J Biol Chem 273: 27505‐27510, 1998.
 118.Kir S, Beddow SA, Samuel VT, Miller P, Previs SF, Suino‐Powell K, Xu HE, Shulman GI, Kliewer SA, Mangelsdorf DJ. FGF19 as a postprandial, insulin‐independent activator of hepatic protein and glycogen synthesis. Science 331: 1621‐1624, 2011.
 119.Knutson SK, Chyla BJ, Amann JM, Bhaskara S, Huppert SS, Hiebert SW. Liver‐specific deletion of histone deacetylase 3 disrupts metabolic transcriptional networks. EMBO J 27: 1017‐1028, 2008.
 120.Konner AC, Janoschek R, Plum L, Jordan SD, Rother E, Ma X, Xu C, Enriori P, Hampel B, Barsh GS, Kahn CR, Cowley MA, Ashcroft FM, Bruning JC. Insulin Action in AgRP‐expressing neurons is required for suppression of hepatic glucose production. Cell Metab 5: 438‐449, 2007.
 121.Koo SH, Flechner L, Qi L, Zhang X, Screaton RA, Jeffries S, Hedrick S, Xu W, Boussouar F, Brindle P, Takemori H, Montminy M. The CREB coactivator TORC2 is a key regulator of fasting glucose metabolism. Nature 437: 1109‐1111, 2005.
 122.Kotoulas OB, Kalamidas SA, Kondomerkos DJ. Glycogen autophagy. Microsc Res Tech 64: 10‐20, 2004.
 123.Kovacs JJ, Murphy PJ, Gaillard S, Zhao X, Wu JT, Nicchitta CV, Yoshida M, Toft DO, Pratt WB, Yao TP. HDAC6 regulates Hsp90 acetylation and chaperone‐dependent activation of glucocorticoid receptor. Molecular cell 18: 601‐607, 2005.
 124.Kulozik P, Jones A, Mattijssen F, Rose AJ, Reimann A, Strzoda D, Kleinsorg S, Raupp C, Kleinschmidt J, Muller‐Decker K, Wahli W, Sticht C, Gretz N, von Loeffelholz C, Stockmann M, Pfeiffer A, Stohr S, Dallinga‐Thie GM, Nawroth PP, Berriel Diaz M, Herzig S. Hepatic deficiency in transcriptional cofactor TBL1 promotes liver steatosis and hypertriglyceridemia. Cell Metab 13: 389‐400, 2011.
 125.Lam TK, Gutierrez‐Juarez R, Pocai A, Bhanot S, Tso P, Schwartz GJ, Rossetti L. Brain glucose metabolism controls the hepatic secretion of triglyceride‐rich lipoproteins. Nat Med 13: 171‐180, 2007.
 126.Lam TK, Gutierrez‐Juarez R, Pocai A, Rossetti L. Regulation of blood glucose by hypothalamic pyruvate metabolism. Science 309: 943‐947, 2005.
 127.Lam TK, Pocai A, Gutierrez‐Juarez R, Obici S, Bryan J, Aguilar‐Bryan L, Schwartz GJ, Rossetti L. Hypothalamic sensing of circulating fatty acids is required for glucose homeostasis. Nat Med 11: 320‐327, 2005.
 128.Lamia KA, Papp SJ, Yu RT, Barish GD, Uhlenhaut NH, Jonker JW, Downes M, Evans RM. Cryptochromes mediate rhythmic repression of the glucocorticoid receptor. Nature 480: 552‐556, 2011.
 129.Lass A, Zimmermann R, Haemmerle G, Riederer M, Schoiswohl G, Schweiger M, Kienesberger P, Strauss JG, Gorkiewicz G, Zechner R. Adipose triglyceride lipase‐mediated lipolysis of cellular fat stores is activated by CGI‐58 and defective in Chanarin‐Dorfman Syndrome. Cell Metab 3: 309‐319, 2006.
 130.Le Lay J, Tuteja G, White P, Dhir R, Ahima R, Kaestner KH. CRTC2 (TORC2) contributes to the transcriptional response to fasting in the liver but is not required for the maintenance of glucose homeostasis. Cell Metab 10: 55‐62, 2009.
 131.Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320: 1492‐1496, 2008.
 132.Lee JH, Giannikopoulos P, Duncan SA, Wang J, Johansen CT, Brown JD, Plutzky J, Hegele RA, Glimcher LH, Lee AH. The transcription factor cyclic AMP‐responsive element‐binding protein H regulates triglyceride metabolism. Nat Med 17: 812‐815, 2011.
 133.Lee JH, Wada T, Febbraio M, He J, Matsubara T, Lee MJ, Gonzalez FJ, Xie W. A novel role for the dioxin receptor in fatty acid metabolism and hepatic steatosis. Gastroenterology 139: 653‐663, 2010.
 134.Lee JM, Lee YK, Mamrosh JL, Busby SA, Griffin PR, Pathak MC, Ortlund EA, Moore DD. A nuclear‐receptor‐dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474: 506‐510, 2011.
 135.Lee MW, Chanda D, Yang J, Oh H, Kim SS, Yoon YS, Hong S, Park KG, Lee IK, Choi CS, Hanson RW, Choi HS, Koo SH. Regulation of hepatic gluconeogenesis by an ER‐bound transcription factor, CREBH. Cell Metab 11: 331‐339, 2010.
 136.Lee SJ, Heinrich G, Fedorova L, Al‐Share QY, Ledford KJ, Fernstrom MA, McInerney MF, Erickson SK, Gatto‐Weis C, Najjar SM. Development of nonalcoholic steatohepatitis in insulin‐resistant liver‐specific S503A carcinoembryonic antigen‐related cell adhesion molecule 1 mutant mice. Gastroenterology 135: 2084‐2095, 2008.
 137.Lee Y, Wang MY, Du XQ, Charron MJ, Unger RH. Glucagon receptor knockout prevents insulin‐deficient type 1 diabetes in mice. Diabetes 60: 391‐397, 2011.
 138.Lee YJ, Ko EH, Kim JE, Kim E, Lee H, Choi H, Yu JH, Kim HJ, Seong JK, Kim KS, Kim JW. Nuclear receptor PPARgamma‐regulated monoacylglycerol O‐acyltransferase 1 (MGAT1) expression is responsible for the lipid accumulation in diet‐induced hepatic steatosis. Proc Natl Acad Sci U S A 109: 13656‐13661, 2012.
 139.Lemke U, Krones‐Herzig A, Berriel Diaz M, Narvekar P, Ziegler A, Vegiopoulos A, Cato AC, Bohl S, Klingmuller U, Screaton RA, Muller‐Decker K, Kersten S, Herzig S. The glucocorticoid receptor controls hepatic dyslipidemia through Hes1. Cell Metab 8: 212‐223, 2008.
 140.Leone TC, Weinheimer CJ, Kelly DP. A critical role for the peroxisome proliferator‐activated receptor alpha (PPARalpha) in the cellular fasting response: the PPARalpha‐null mouse as a model of fatty acid oxidation disorders. Proc Natl Acad Sci U S A 96: 7473‐7478, 1999.
 141.Lerin C, Rodgers JT, Kalume DE, Kim SH, Pandey A, Puigserver P. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC‐1alpha. Cell Metab 3: 429‐438, 2006.
 142.Lewis JR, Mohanty SR. Nonalcoholic fatty liver disease: A review and update. Dig Dis Sci 55: 560‐578, 2010.
 143.Li LO, Ellis JM, Paich HA, Wang S, Gong N, Altshuller G, Thresher RJ, Koves TR, Watkins SM, Muoio DM, Cline GW, Shulman GI, Coleman RA. Liver‐specific loss of long chain acyl‐CoA synthetase‐1 decreases triacylglycerol synthesis and beta‐oxidation and alters phospholipid fatty acid composition. J Biol Chem 284: 27816‐27826, 2009.
 144.Li S, Brown MS, Goldstein JL. Bifurcation of insulin signaling pathway in rat liver: mTORC1 required for stimulation of lipogenesis, but not inhibition of gluconeogenesis. Proc Natl Acad Sci U S A 107: 3441‐3446, 2010.
 145.Li S, Liu C, Li N, Hao T, Han T, Hill DE, Vidal M, Lin JD. Genome‐wide coactivation analysis of PGC‐1alpha identifies BAF60a as a regulator of hepatic lipid metabolism. Cell Metab 8: 105‐117, 2008.
 146.Li X, Monks B, Ge Q, Birnbaum MJ. Akt/PKB regulates hepatic metabolism by directly inhibiting PGC‐1alpha transcription coactivator. Nature 447: 1012‐1016, 2007.
 147.Li Y, Xu S, Mihaylova MM, Zheng B, Hou X, Jiang B, Park O, Luo Z, Lefai E, Shyy JY, Gao B, Wierzbicki M, Verbeuren TJ, Shaw RJ, Cohen RA, Zang M. AMPK phosphorylates and inhibits SREBP activity to attenuate hepatic steatosis and atherosclerosis in diet‐induced insulin‐resistant mice. Cell Metab 13: 376‐388, 2011.
 148.Liang Y, Osborne MC, Monia BP, Bhanot S, Gaarde WA, Reed C, She P, Jetton TL, Demarest KT. Reduction in glucagon receptor expression by an antisense oligonucleotide ameliorates diabetic syndrome in db/db mice. Diabetes 53: 410‐417, 2004.
 149.Lin J, Yang R, Tarr PT, Wu PH, Handschin C, Li S, Yang W, Pei L, Uldry M, Tontonoz P, Newgard CB, Spiegelman BM. Hyperlipidemic effects of dietary saturated fats mediated through PGC‐1beta coactivation of SREBP. Cell 120: 261‐273, 2005.
 150.Lin Z, Tian H, Lam KS, Lin S, Hoo RC, Konishi M, Itoh N, Wang Y, Bornstein SR, Xu A, Li X. Adiponectin mediates the metabolic effects of FGF21 on glucose homeostasis and insulin sensitivity in mice. Cell Metab 17: 779‐789, 2013.
 151.Liu H, Fergusson MM, Wu JJ, Rovira, II, Liu J, Gavrilova O, Lu T, Bao J, Han D, Sack MN, Finkel T. Wnt signaling regulates hepatic metabolism. Sci Signal 4: ra6, 2011.
 152.Liu S, Croniger C, Arizmendi C, Harada‐Shiba M, Ren J, Poli V, Hanson RW, Friedman JE. Hypoglycemia and impaired hepatic glucose production in mice with a deletion of the C/EBPbeta gene. J Clin Invest 103: 207‐213, 1999.
 153.Liu S, Hatano B, Zhao M, Yen CC, Kang K, Reilly SM, Gangl MR, Gorgun C, Balschi JA, Ntambi JM, Lee CH. Role of peroxisome proliferator‐activated receptor {delta}/{beta} in hepatic metabolic regulation. J Biol Chem 286: 1237‐1247, 2011.
 154.Liu Y, Dentin R, Chen D, Hedrick S, Ravnskjaer K, Schenk S, Milne J, Meyers DJ, Cole P, Yates J, III, Olefsky J, Guarente L, Montminy M. A fasting inducible switch modulates gluconeogenesis via activator/coactivator exchange. Nature 456: 269‐273, 2008.
 155.Liu Y, Yan C, Wang Y, Nakagawa Y, Nerio N, Anghel A, Lutfy K, Friedman TC. Liver X receptor agonist T0901317 inhibition of glucocorticoid receptor expression in hepatocytes may contribute to the amelioration of diabetic syndrome in db/db mice. Endocrinology 147: 5061‐5068, 2006.
 156.Longuet C, Sinclair EM, Maida A, Baggio LL, Maziarz M, Charron MJ, Drucker DJ. The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metabolism 8: 359‐371, 2008.
 157.Louet JF, Chopra AR, Sagen JV, An J, York B, Tannour‐Louet M, Saha PK, Stevens RD, Wenner BR, Ilkayeva OR, Bain JR, Zhou S, DeMayo F, Xu J, Newgard CB, O'Malley BW. The coactivator SRC‐1 is an essential coordinator of hepatic glucose production. Cell Metab 12: 606‐618, 2010.
 158.Lu M, Wan M, Leavens KF, Chu Q, Monks BR, Fernandez S, Ahima RS, Ueki K, Kahn CR, Birnbaum MJ. Insulin regulates liver metabolism in vivo in the absence of hepatic Akt and Foxo1. Nat Med 18: 388‐395, 2012.
 159.Lu Y, Xiong X, Wang X, Zhang Z, Li J, Shi G, Yang J, Zhang H, Ning G, Li X. Yin Yang 1 promotes hepatic gluconeogenesis through upregulation of glucocorticoid receptor. Diabetes 62: 1064‐1073, 2013.
 160.Lustig Y, Ruas JL, Estall JL, Lo JC, Devarakonda S, Laznik D, Choi JH, Ono H, Olsen JV, Spiegelman BM. Separation of the gluconeogenic and mitochondrial functions of PGC‐1{alpha} through S6 kinase. Genes Dev 25: 1232‐1244, 2011.
 161.Magnusson I, Rothman DL, Katz LD, Shulman RG, Shulman GI. Increased rate of gluconeogenesis in type II diabetes mellitus. A 13C nuclear magnetic resonance study. J Clin Invest 90: 1323‐1327, 1992.
 162.Mao J, DeMayo FJ, Li H, Abu‐Elheiga L, Gu Z, Shaikenov TE, Kordari P, Chirala SS, Heird WC, Wakil SJ. Liver‐specific deletion of acetyl‐CoA carboxylase 1 reduces hepatic triglyceride accumulation without affecting glucose homeostasis. Proc Natl Acad Sci U S A 103: 8552‐8557, 2006.
 163.Mao T, Shao M, Qiu Y, Huang J, Zhang Y, Song B, Wang Q, Jiang L, Liu Y, Han JD, Cao P, Li J, Gao X, Rui L, Qi L, Li W. PKA phosphorylation couples hepatic inositol‐requiring enzyme 1alpha to glucagon signaling in glucose metabolism. Proc Natl Acad Sci U S A 108: 15852‐15857, 2011.
 164.Martin GG, Danneberg H, Kumar LS, Atshaves BP, Erol E, Bader M, Schroeder F, Binas B. Decreased liver fatty acid binding capacity and altered liver lipid distribution in mice lacking the liver fatty acid‐binding protein gene. J Biol Chem 278: 21429‐21438, 2003.
 165.Matsukuma KE, Bennett MK, Huang J, Wang L, Gil G, Osborne TF. Coordinated control of bile acids and lipogenesis through FXR‐dependent regulation of fatty acid synthase. J Lipid Res 47: 2754‐2761, 2006.
 166.Matsumoto M, Pocai A, Rossetti L, Depinho RA, Accili D. Impaired regulation of hepatic glucose production in mice lacking the forkhead transcription factor Foxo1 in liver. Cell Metab 6: 208‐216, 2007.
 167.Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, Brewer B, Jr., Reitman ML, Gonzalez FJ. Liver‐specific disruption of PPARgamma in leptin‐deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 111: 737‐747, 2003.
 168.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.
 169.Matsuzaka T, Atsumi A, Matsumori R, Nie T, Shinozaki H, Suzuki‐Kemuriyama N, Kuba M, Nakagawa Y, Ishii K, Shimada M, Kobayashi K, Yatoh S, Takahashi A, Takekoshi K, Sone H, Yahagi N, Suzuki H, Murata S, Nakamuta M, Yamada N, Shimano H. Elovl6 promotes nonalcoholic steatohepatitis. Hepatology 56: 2199‐2208, 2012.
 170.Matsuzaki H, Daitoku H, Hatta M, Aoyama H, Yoshimochi K, Fukamizu A. Acetylation of Foxo1 alters its DNA‐binding ability and sensitivity to phosphorylation. Proc Natl Acad Sci U S A 102: 11278‐11283, 2005.
 171.Merla G, Howald C, Antonarakis SE, Reymond A. The subcellular localization of the ChoRE‐binding protein, encoded by the Williams‐Beuren syndrome critical region gene 14, is regulated by 14‐3‐3. Human molecular genetics 13: 1505‐1514, 2004.
 172.Meyer C, Stumvoll M, Nadkarni V, Dostou J, Mitrakou A, Gerich J. Abnormal renal and hepatic glucose metabolism in type 2 diabetes mellitus. J Clin Invest 102: 619‐624, 1998.
 173.Michael MD, Kulkarni RN, Postic C, Previs SF, Shulman GI, Magnuson MA, Kahn CR. Loss of insulin signaling in hepatocytes leads to severe insulin resistance and progressive hepatic dysfunction. Molecular cell 6: 87‐97, 2000.
 174.Mihaylova MM, Vasquez DS, Ravnskjaer K, Denechaud PD, Yu RT, Alvarez JG, Downes M, Evans RM, Montminy M, Shaw RJ. Class IIa histone deacetylases are hormone‐activated regulators of FOXO and mammalian glucose homeostasis. Cell 145: 607‐621, 2011.
 175.Miyazaki M, Flowers MT, Sampath H, Chu K, Otzelberger C, Liu X, Ntambi JM. Hepatic stearoyl‐CoA desaturase‐1 deficiency protects mice from carbohydrate‐induced adiposity and hepatic steatosis. Cell Metab 6: 484‐496, 2007.
 176.Molusky MM, Li S, Ma D, Yu L, Lin JD. Ubiquitin‐specific protease 2 regulates hepatic gluconeogenesis and diurnal glucose metabolism through 11beta‐hydroxysteroid dehydrogenase 1. Diabetes 61: 1025‐1035, 2012.
 177.Moon YA, Liang G, Xie X, Frank‐Kamenetsky M, Fitzgerald K, Koteliansky V, Brown MS, Goldstein JL, Horton JD. The Scap/SREBP pathway is essential for developing diabetic fatty liver and carbohydrate‐induced hypertriglyceridemia in animals. Cell Metab 15: 240‐246, 2012.
 178.Moran‐Salvador E, Lopez‐Parra M, Garcia‐Alonso V, Titos E, Martinez‐Clemente M, Gonzalez‐Periz A, Lopez‐Vicario C, Barak Y, Arroyo V, Claria J. Role for PPARgamma in obesity‐induced hepatic steatosis as determined by hepatocyte‐ and macrophage‐specific conditional knockouts. FASEB J 25: 2538‐2550, 2011.
 179.Morris DL, Cho KW, Zhou Y, Rui L. SH2B1 enhances insulin sensitivity by both stimulating the insulin receptor and inhibiting tyrosine dephosphorylation of insulin receptor substrate proteins. Diabetes 58: 2039‐2047, 2009.
 180.Morris DL Rui L. Recent advances in understanding leptin signaling and leptin resistance. Am J Physiol Endocrinol Metab 297: E1247‐E1259, 2009.
 181.Mostoslavsky R, Chua KF, Lombard DB, Pang WW, Fischer MR, Gellon L, Liu P, Mostoslavsky G, Franco S, Murphy MM, Mills KD, Patel P, Hsu JT, Hong AL, Ford E, Cheng HL, Kennedy C, Nunez N, Bronson R, Frendewey D, Auerbach W, Valenzuela D, Karow M, Hottiger MO, Hursting S, Barrett JC, Guarente L, Mulligan R, Demple B, Yancopoulos GD, Alt FW. Genomic instability and aging‐like phenotype in the absence of mammalian SIRT6. Cell 124: 315‐329, 2006.
 182.Mueller KM, Themanns M, Friedbichler K, Kornfeld JW, Esterbauer H, Tuckermann JP, Moriggl R. Hepatic growth hormone and glucocorticoid receptor signaling in body growth, steatosis and metabolic liver cancer development. Mol Cell Endocrinol 361: 1‐11, 2012.
 183.Mutel E, Abdul‐Wahed A, Ramamonjisoa N, Stefanutti A, Houberdon I, Cavassila S, Pilleul F, Beuf O, Gautier‐Stein A, Penhoat A, Mithieux G, Rajas F. Targeted deletion of liver glucose‐6 phosphatase mimics glycogen storage disease type 1a including development of multiple adenomas. Journal of hepatology 54: 529‐537, 2011.
 184.Nader N, Ng SS, Wang Y, Abel BS, Chrousos GP, Kino T. Liver x receptors regulate the transcriptional activity of the glucocorticoid receptor: Implications for the carbohydrate metabolism. PLoS One 7: e26751, 2012.
 185.Nagai Y, Yonemitsu S, Erion DM, Iwasaki T, Stark R, Weismann D, Dong J, Zhang D, Jurczak MJ, Loffler MG, Cresswell J, Yu XX, Murray SF, Bhanot S, Monia BP, Bogan JS, Samuel V, Shulman GI. The role of peroxisome proliferator‐activated receptor gamma coactivator‐1 beta in the pathogenesis of fructose‐induced insulin resistance. Cell Metab 9: 252‐264, 2009.
 186.Najjar SM, Yang Y, Fernstrom MA, Lee SJ, Deangelis AM, Rjaily GA, Al‐Share QY, Dai T, Miller TA, Ratnam S, Ruch RJ, Smith S, Lin SH, Beauchemin N, Oyarce AM. Insulin acutely decreases hepatic fatty acid synthase activity. Cell Metab 2: 43‐53, 2005.
 187.Nakae J, Kitamura T, Silver DL, Accili D. The forkhead transcription factor Foxo1 (Fkhr) confers insulin sensitivity onto glucose‐6‐phosphatase expression. J Clin Invest 108: 1359‐1367, 2001.
 188.Nakagawa T, Lomb DJ, Haigis MC, Guarente L. SIRT5 Deacetylates carbamoyl phosphate synthetase 1 and regulates the urea cycle. Cell 137: 560‐570, 2009.
 189.Newberry EP, Xie Y, Kennedy S, Han X, Buhman KK, Luo J, Gross RW, Davidson NO. Decreased hepatic triglyceride accumulation and altered fatty acid uptake in mice with deletion of the liver fatty acid‐binding protein gene. J Biol Chem 278: 51664‐51672, 2003.
 190.Newberry EP, Xie Y, Kennedy SM, Luo J, Davidson NO. Protection against Western diet‐induced obesity and hepatic steatosis in liver fatty acid‐binding protein knockout mice. Hepatology 44: 1191‐1205, 2006.
 191.Nie Y, Erion DM, Yuan Z, Dietrich M, Shulman GI, Horvath TL, Gao Q. STAT3 inhibition of gluconeogenesis is downregulated by SirT1. Nat Cell Biol 11: 492‐500, 2009.
 192.Ning J, Hong T, Ward A, Pi J, Liu Z, Liu HY, Cao W. Constitutive role for IRE1alpha‐XBP1 signaling pathway in the insulin‐mediated hepatic lipogenic program. Endocrinology 152: 2247‐2255, 2011.
 193.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.
 194.Obici S, Feng Z, Karkanias G, Baskin DG, Rossetti L. Decreasing hypothalamic insulin receptors causes hyperphagia and insulin resistance in rats. 5: 566‐572, 2002.
 195.Obici S, Feng Z, Morgan K, Stein D, Karkanias G, Rossetti L. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51: 271‐275, 2002.
 196.Obici S, Zhang BB, Karkanias G, Rossetti L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat Med 8: 1376‐1382, 2002.
 197.Okar DA, Manzano A, Navarro‐Sabate A, Riera L, Bartrons R, Lange AJ. PFK‐2/FBPase‐2: maker and breaker of the essential biofactor fructose‐2,6‐bisphosphate. Trends Biochem Sci 26: 30‐35, 2001.
 198.Oosterveer MH, Mataki C, Yamamoto H, Harach T, Moullan N, van Dijk TH, Ayuso E, Bosch F, Postic C, Groen AK, Auwerx J, Schoonjans K. LRH‐1‐dependent glucose sensing determines intermediary metabolism in liver. J Clin Invest 122: 2817‐2826, 2012.
 199.Opherk C, Tronche F, Kellendonk C, Kohlmuller D, Schulze A, Schmid W, Schutz G. Inactivation of the glucocorticoid receptor in hepatocytes leads to fasting hypoglycemia and ameliorates hyperglycemia in streptozotocin‐induced diabetes mellitus. Mol Endocrinol 18: 1346‐1353, 2004.
 200.Oyadomari S, Harding HP, Zhang Y, Oyadomari M, Ron D. Dephosphorylation of translation initiation factor 2alpha enhances glucose tolerance and attenuates hepatosteatosis in mice. Cell Metab 7: 520‐532, 2008.
 201.Ozcan L, Wong CC, Li G, Xu T, Pajvani U, Park SK, Wronska A, Chen BX, Marks AR, Fukamizu A, Backs J, Singer HA, Yates JR, III, Accili D, Tabas I. Calcium signaling through CaMKII regulates hepatic glucose production in fasting and obesity. Cell Metab 15: 739‐751, 2012.
 202.Ozcan U, Cao Q, Yilmaz E, Lee AH, Iwakoshi NN, Ozdelen E, Tuncman G, Gorgun C, Glimcher LH, Hotamisligil GS. Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes. Science 306: 457‐461, 2004.
 203.Pagadala M, Kasumov T, McCullough AJ, Zein NN, Kirwan JP. Role of ceramides in nonalcoholic fatty liver disease. Trends Endocrinol Metabol 23: 365‐371, 2012.
 204.Pal D, Dasgupta S, Kundu R, Maitra S, Das G, Mukhopadhyay S, Ray S, Majumdar SS, Bhattacharya S. Fetuin‐A acts as an endogenous ligand of TLR4 to promote lipid‐induced insulin resistance. Nat Med 18: 1279‐1285, 2012.
 205.Parker JC, Andrews KM, Allen MR, Stock JL, McNeish JD. Glycemic control in mice with targeted disruption of the glucagon receptor gene. Biochem Biophys Res Commun 290: 839‐843, 2002.
 206.Patel R, Patel M, Tsai R, Lin V, Bookout AL, Zhang Y, Magomedova L, Li T, Chan JF, Budd C, Mangelsdorf DJ, Cummins CL. LXRbeta is required for glucocorticoid‐induced hyperglycemia and hepatosteatosis in mice. J Clin Invest 121: 431‐441, 2011.
 207.Peterson TR, Sengupta SS, Harris TE, Carmack AE, Kang SA, Balderas E, Guertin DA, Madden KL, Carpenter AE, Finck BN, Sabatini DM. mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway. Cell 146: 408‐420, 2011.
 208.Pineda Torra I, Claudel T, Duval C, Kosykh V, Fruchart JC, Staels B. Bile acids induce the expression of the human peroxisome proliferator‐activated receptor alpha gene via activation of the farnesoid X receptor. Mol Endocrinol 17: 259‐272, 2003.
 209.Ponugoti B, Kim DH, Xiao Z, Smith Z, Miao J, Zang M, Wu SY, Chiang CM, Veenstra TD, Kemper JK. SIRT1 deacetylates and inhibits SREBP‐1C activity in regulation of hepatic lipid metabolism. J Biol Chem 285: 33959‐33970, 2010.
 210.Postic C, Shiota M, Niswender KD, Jetton TL, Chen Y, Moates JM, Shelton KD, Lindner J, Cherrington AD, Magnuson MA. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell‐specific gene knock‐outs using Cre recombinase. J Biol Chem 274: 305‐315, 1999.
 211.Potthoff MJ, Boney‐Montoya J, Choi M, He T, Sunny NE, Satapati S, Suino‐Powell K, Xu HE, Gerard RD, Finck BN, Burgess SC, Mangelsdorf DJ, Kliewer SA. FGF15/19 regulates hepatic glucose metabolism by inhibiting the CREB‐PGC‐1alpha pathway. Cell Metab 13: 729‐738, 2011.
 212.Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA, Burgess SC. FGF21 induces PGC‐1alpha and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 106: 10853‐10858, 2009.
 213.Poy MN, Yang Y, Rezaei K, Fernstrom MA, Lee AD, Kido Y, Erickson SK, Najjar SM. CEACAM1 regulates insulin clearance in liver. Nat Genet 30: 270‐276, 2002.
 214.Puigserver P, Rhee J, Donovan J, Walkey CJ, Yoon JC, Oriente F, Kitamura Y, Altomonte J, Dong H, Accili D, Spiegelman BM. Insulin‐regulated hepatic gluconeogenesis through FOXO1‐PGC‐1alpha interaction. Nature 423: 550‐555, 2003.
 215.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.
 216.Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X. Hepatocyte‐specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9: 327‐338, 2009.
 217.Rahman SM, Schroeder‐Gloeckler JM, Janssen RC, Jiang H, Qadri I, Maclean KN, Friedman JE. CCAAT/enhancing binding protein beta deletion in mice attenuates inflammation, endoplasmic reticulum stress, and lipid accumulation in diet‐induced nonalcoholic steatohepatitis. Hepatology 45: 1108‐1117, 2007.
 218.Rajala MW, Scherer PE. Minireview: The adipocyte–at the crossroads of energy homeostasis, inflammation, and atherosclerosis. Endocrinology 144: 3765‐3773, 2003.
 219.Ramadoss P, Unger‐Smith NE, Lam FS, Hollenberg AN. STAT3 targets the regulatory regions of gluconeogenic genes in vivo. Mol Endocrinol 23: 827‐837, 2009.
 220.Ramnanan CJ, Saraswathi V, Smith MS, Donahue EP, Farmer B, Farmer TD, Neal D, Williams PE, Lautz M, Mari A, Cherrington AD, Edgerton DS. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs. J Clin Invest 121: 3713‐3723, 2011.
 221.Reddy JK, Rao MS. Lipid metabolism and liver inflammation. II. Fatty liver disease and fatty acid oxidation. Am J Physiol Gastrointest Liver Physiol 290: G852‐G858, 2006.
 222.Ren D, Li M, Duan C, Rui L. Identification of SH2‐B as a key regulator of leptin sensitivity, energy balance, and body weight in mice. Cell Metabolism 2: 95‐104, 2005.
 223.Ren D, Zhou Y, Morris D, Li M, Li Z, Rui L. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis. J Clin Invest 117: 397‐406, 2007.
 224.Repa JJ, Liang G, Ou J, Bashmakov Y, Lobaccaro JM, Shimomura I, Shan B, Brown MS, Goldstein JL, Mangelsdorf DJ. Regulation of mouse sterol regulatory element‐binding protein‐1c gene (SREBP‐1c) by oxysterol receptors, LXRalpha and LXRbeta. Genes Dev 14: 2819‐2830, 2000.
 225.Rider MH, Bertrand L, Vertommen D, Michels PA, Rousseau GG, Hue L. 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase: Head‐to‐head with a bifunctional enzyme that controls glycolysis. Biochem J 381: 561‐579, 2004.
 226.Rodgers JT, Lerin C, Haas W, Gygi SP, Spiegelman BM, Puigserver P. Nutrient control of glucose homeostasis through a complex of PGC‐1alpha and SIRT1. Nature 434: 113‐118, 2005.
 227.Rodgers JT, Puigserver P. Fasting‐dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci U S A 104: 12861‐12866, 2007.
 228.Rui L, Yuan M, Frantz D, Shoelson S, White MF. SOCS‐1 and SOCS‐3 Block insulin signaling by ubiquitin‐mediated degradation of IRS1 and IRS2. J Biol Chem 277: 42394‐42398, 2002.
 229.Rutkowski DT, Wu J, Back SH, Callaghan MU, Ferris SP, Iqbal J, Clark R, Miao H, Hassler JR, Fornek J, Katze MG, Hussain MM, Song B, Swathirajan J, Wang J, Yau GD, Kaufman RJ. UPR pathways combine to prevent hepatic steatosis caused by ER stress‐mediated suppression of transcriptional master regulators. Developmental cell 15: 829‐840, 2008.
 230.Sabio G, Cavanagh‐Kyros J, Ko HJ, Jung DY, Gray S, Jun JY, Barrett T, Mora A, Kim JK, Davis RJ. Prevention of steatosis by hepatic JNK1. Cell Metab 10: 491‐498, 2009.
 231.Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, Barrett T, Kim JK, Davis RJ. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322: 1539‐1543, 2008.
 232.Sakiyama H, Wynn RM, Lee WR, Fukasawa M, Mizuguchi H, Gardner KH, Repa JJ, Uyeda K. Regulation of nuclear import/export of carbohydrate response element‐binding protein (ChREBP): Interaction of an alpha‐helix of ChREBP with the 14‐3‐3 proteins and regulation by phosphorylation. J Biol Chem 283: 24899‐24908, 2008.
 233.Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature 414: 799‐806, 2001.
 234.Sanderson LM, Degenhardt T, Koppen A, Kalkhoven E, Desvergne B, Muller M, Kersten S. Peroxisome proliferator‐activated receptor beta/delta (PPARbeta/delta) but not PPARalpha serves as a plasma free fatty acid sensor in liver. Mol Cell Biol 29: 6257‐6267, 2009.
 235.Santoro N, Zhang CK, Zhao H, Pakstis AJ, Kim G, Kursawe R, Dykas DJ, Bale AE, Giannini C, Pierpont B, Shaw MM, Groop L, Caprio S. Variant in the glucokinase regulatory protein (GCKR) gene is associated with fatty liver in obese children and adolescents. Hepatology 55: 781‐789, 2012.
 236.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.
 237.Schroeder‐Gloeckler JM, Rahman SM, Janssen RC, Qiao L, Shao J, Roper M, Fischer SJ, Lowe E, Orlicky DJ, McManaman JL, Palmer C, Gitomer WL, Huang W, O'Doherty RM, Becker TC, Klemm DJ, Jensen DR, Pulawa LK, Eckel RH, Friedman JE. CCAAT/enhancer‐binding protein beta deletion reduces adiposity, hepatic steatosis, and diabetes in Lepr(db/db) mice. J Biol Chem 282: 15717‐15729, 2007.
 238.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.
 239.Sekine K, Chen YR, Kojima N, Ogata K, Fukamizu A, Miyajima A. Foxo1 links insulin signaling to C/EBPalpha and regulates gluconeogenesis during liver development. EMBO J 26: 3607‐3615, 2007.
 240.Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM. mTORC1 controls fasting‐induced ketogenesis and its modulation by ageing. Nature 468: 1100‐1104, 2010.
 241.Seyer P, Vallois D, Poitry‐Yamate C, Schutz F, Metref S, Tarussio D, Maechler P, Staels B, Lanz B, Grueter R, Decaris J, Turner S, da Costa A, Preitner F, Minehira K, Foretz M, Thorens B. Hepatic glucose sensing is required to preserve beta cell glucose competence. J Clin Invest 123: 1662‐1676, 2013.
 242.Shaw RJ, Lamia KA, Vasquez D, Koo SH, Bardeesy N, Depinho RA, Montminy M, Cantley LC. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310: 1642‐1646, 2005.
 243.She P, Shiota M, Shelton KD, Chalkley R, Postic C, Magnuson MA. Phosphoenolpyruvate carboxykinase is necessary for the integration of hepatic energy metabolism. Mol Cell Biol 20: 6508‐6517, 2000.
 244.Sheng L, Zhou Y, Chen Z, Ren D, Cho KW, Jiang L, Shen H, Sasaki Y, Rui L. NF‐kappaB‐inducing kinase (NIK) promotes hyperglycemia and glucose intolerance in obesity by augmenting glucagon action. Nat Med 18: 943‐949, 2012.
 245.Shi H, Kokoeva MV, Inouye K, Tzameli I, Yin H, Flier JS. TLR4 links innate immunity and fatty acid‐induced insulin resistance. J Clin Invest 116: 3015‐3025, 2006.
 246.Shimazu T, Hirschey MD, Hua L, Dittenhafer‐Reed KE, Schwer B, Lombard DB, Li Y, Bunkenborg J, Alt FW, Denu JM, Jacobson MP, Verdin E. SIRT3 deacetylates mitochondrial 3‐hydroxy‐3‐methylglutaryl CoA synthase 2 and regulates ketone body production. Cell Metab 12: 654‐661, 2010.
 247.Sinal CJ, Tohkin M, Miyata M, Ward JM, Lambert G, Gonzalez FJ. Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis. Cell 102: 731‐744, 2000.
 248.Sloop KW, Cao JX, Siesky AM, Zhang HY, Bodenmiller DM, Cox AL, Jacobs SJ, Moyers JS, Owens RA, Showalter AD, Brenner MB, Raap A, Gromada J, Berridge BR, Monteith DK, Porksen N, McKay RA, Monia BP, Bhanot S, Watts LM, Michael MD. Hepatic and glucagon‐like peptide‐1‐mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 113: 1571‐1581, 2004.
 249.So JS, Hur KY, Tarrio M, Ruda V, Frank‐Kamenetsky M, Fitzgerald K, Koteliansky V, Lichtman AH, Iwawaki T, Glimcher LH, Lee AH. Silencing of lipid metabolism genes through IRE1alpha‐mediated mRNA decay lowers plasma lipids in mice. Cell Metab 16: 487‐499, 2012.
 250.Sos BC, Harris C, Nordstrom SM, Tran JL, Balazs M, Caplazi P, Febbraio M, Applegate MA, Wagner KU, Weiss EJ. Abrogation of growth hormone secretion rescues fatty liver in mice with hepatocyte‐specific deletion of JAK2. J Clin Invest 121: 1412‐1423, 2011.
 251.Spruss A, Kanuri G, Wagnerberger S, Haub S, Bischoff SC, Bergheim I. Toll‐like receptor 4 is involved in the development of fructose‐induced hepatic steatosis in mice. Hepatology 50: 1094‐1104, 2009.
 252.Stanley S, Pinto S, Segal J, Perez CA, Viale A, DeFalco J, Cai X, Heisler LK, Friedman JM. Identification of neuronal subpopulations that project from hypothalamus to both liver and adipose tissue polysynaptically. Proc Natl Acad Sci U S A 107: 7024‐7029, 2010.
 253.Stanya KJ, Jacobi D, Liu S, Bhargava P, Dai L, Gangl MR, Inouye K, Barlow JL, Ji Y, Mizgerd JP, Qi L, Shi H, McKenzie AN, Lee CH. Direct control of hepatic glucose production by interleukin‐13 in mice. J Clin Invest 123: 261‐271, 2013.
 254.Stoeckman AK, Ma L, Towle HC. Mlx is the functional heteromeric partner of the carbohydrate response element‐binding protein in glucose regulation of lipogenic enzyme genes. J Biol Chem 279: 15662‐15669, 2004.
 255.Storey SM, McIntosh AL, Huang H, Martin GG, Landrock KK, Landrock D, Payne HR, Kier AB, Schroeder F. Loss of intracellular lipid binding proteins differentially impacts saturated fatty acid uptake and nuclear targeting in mouse hepatocytes. Am J Physiol Gastrointest Liver Physiol 303: G837‐G850, 2012.
 256.Su Y, Lam TK, He W, Pocai A, Bryan J, Aguilar‐Bryan L, and Gutierrez‐Juarez R. Hypothalamic leucine metabolism regulates liver glucose production. Diabetes 61: 85‐93, 2012.
 257.Sumara G, Sumara O, Kim JK, Karsenty G. Gut‐derived serotonin is a multifunctional determinant to fasting adaptation. Cell Metab 16: 588‐600, 2012.
 258.Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 14: 804‐810, 2011.
 259.Teodoro JS, Rolo AP, Palmeira CM. Hepatic FXR: key regulator of whole‐body energy metabolism. Trends Endocrinol Metabol 22: 458‐466, 2011.
 260.Tobin KA, Ulven SM, Schuster GU, Steineger HH, Andresen SM, Gustafsson JA, Nebb HI. Liver X receptors as insulin‐mediating factors in fatty acid and cholesterol biosynthesis. J Biol Chem 277: 10691‐10697, 2002.
 261.Tong Q, Ye C, McCrimmon RJ, Dhillon H, Choi B, Kramer MD, Yu J, Yang Z, Christiansen LM, Lee CE, Choi CS, Zigman JM, Shulman GI, Sherwin RS, Elmquist JK, Lowell BB. Synaptic glutamate release by ventromedial hypothalamic neurons is part of the neurocircuitry that prevents hypoglycemia. Cell Metab 5: 383‐393, 2007.
 262.Torres TP, Catlin RL, Chan R, Fujimoto Y, Sasaki N, Printz RL, Newgard CB, Shiota M. Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats. Diabetes 58: 78‐86, 2009.
 263.Ueki K, Kondo T, Kahn CR. Suppressor of cytokine signaling 1 (SOCS‐1) and SOCS‐3 cause insulin resistance through inhibition of tyrosine phosphorylation of insulin receptor substrate proteins by discrete mechanisms. Mol Cell Biol 24: 5434‐5446, 2004.
 264.Unger RH, Cherrington AD. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J Clin Invest 122: 4‐12, 2012.
 265.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.
 266.Vega RB, Huss JM, Kelly DP. The coactivator PGC‐1 cooperates with peroxisome proliferator‐activated receptor alpha in transcriptional control of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 20: 1868‐1876, 2000.
 267.Vegiopoulos A, Herzig S. Glucocorticoids, metabolism and metabolic diseases. Mol Cell Endocrinol 275: 43‐61, 2007.
 268.Walker AK, Jacobs RL, Watts JL, Rottiers V, Jiang K, Finnegan DM, Shioda T, Hansen M, Yang F, Niebergall LJ, Vance DE, Tzoneva M, Hart AC, Naar AM. A conserved SREBP‐1/phosphatidylcholine feedback circuit regulates lipogenesis in metazoans. Cell 147: 840‐852, 2011.
 269.Walker AK, Yang F, Jiang K, Ji JY, Watts JL, Purushotham A, Boss O, Hirsch ML, Ribich S, Smith JJ, Israelian K, Westphal CH, Rodgers JT, Shioda T, Elson SL, Mulligan P, Najafi‐Shoushtari H, Black JC, Thakur JK, Kadyk LC, Whetstine JR, Mostoslavsky R, Puigserver P, Li X, Dyson NJ, Hart AC, Naar AM. Conserved role of SIRT1 orthologs in fasting‐dependent inhibition of the lipid/cholesterol regulator SREBP. Genes Dev 24: 1403‐1417, 2010.
 270.Wan M, Leavens KF, Saleh D, Easton RM, Guertin DA, Peterson TR, Kaestner KH, Sabatini DM, Birnbaum MJ. Postprandial hepatic lipid metabolism requires signaling through Akt2 independent of the transcription factors FoxA2, FoxO1, and SREBP1c. Cell Metab 14: 516‐527, 2011.
 271.Wang ND, Finegold MJ, Bradley A, Ou CN, Abdelsayed SV, Wilde MD, Taylor LR, Wilson DR, Darlington GJ. Impaired energy homeostasis in C/EBP alpha knockout mice. Science 269: 1108‐1112, 1995.
 272.Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, Gutierrez‐Juarez R, Ang M, Schwartz GJ, Lam TK. Upper intestinal lipids trigger a gut‐brain‐liver axis to regulate glucose production. Nature 452: 1012‐1016, 2008.
 273.Wang RH, Kim HS, Xiao C, Xu X, Gavrilova O, Deng CX. Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance. J Clin Invest 121: 4477‐4490, 2011.
 274.Wang Y, Inoue H, Ravnskjaer K, Viste K, Miller N, Liu Y, Hedrick S, Vera L, Montminy M. Targeted disruption of the CREB coactivator Crtc2 increases insulin sensitivity. Proc Natl Acad Sci U S A 107: 3087‐3092, 2010.
 275.Wang Y, Li G, Goode J, Paz JC, Ouyang K, Screaton R, Fischer WH, Chen J, Tabas I, Montminy M. Inositol‐1,4,5‐trisphosphate receptor regulates hepatic gluconeogenesis in fasting and diabetes. Nature, 2012.
 276.Wang Y, Vera L, Fischer WH, Montminy M. The CREB coactivator CRTC2 links hepatic ER stress and fasting gluconeogenesis. Nature 460: 534‐537, 2009.
 277.Warne JP, Alemi F, Reed AS, Varonin JM, Chan H, Piper ML, Mullin ME, Myers MG, Jr., Corvera CU, and Xu AW. Impairment of central leptin‐mediated PI3K signaling manifested as hepatic steatosis independent of hyperphagia and obesity. Cell Metab 14: 791‐803, 2011.
 278.Wasserman DH, Spalding JA, Lacy DB, Colburn CA, Goldstein RE, Cherrington AD. Glucagon is a primary controller of hepatic glycogenolysis and gluconeogenesis during muscular work. Am J Physiol 257: E108‐117, 1989.
 279.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.
 280.Wei D, Tao R, Zhang Y, White MF, Dong XC. Feedback regulation of hepatic gluconeogenesis through modulation of SHP/Nr0b2 gene expression by Sirt1 and FoxO1. Am J Physiol Endocrinol Metab 300: E312‐320, 2011.
 281.Wei Z, Peterson JM, Lei X, Cebotaru L, Wolfgang MJ, Baldeviano GC, Wong GW. C1q/TNF‐related protein‐12 (CTRP12), a novel adipokine that improves insulin sensitivity and glycemic control in mouse models of obesity and diabetes. J Biol Chem 287: 10301‐10315, 2012.
 282.White MF. IRS proteins and the common path to diabetes. Am J Physiol Endocrinol Metab 283: E413‐422, 2002.
 283.Winkler R, Benz V, Clemenz M, Bloch M, Foryst‐Ludwig A, Wardat S, Witte N, Trappiel M, Namsolleck P, Mai K, Spranger J, Matthias G, Roloff T, Truee O, Kappert K, Schupp M, Matthias P, Kintscher U. Histone deacetylase 6 (HDAC6) is an essential modifier of glucocorticoid‐induced hepatic gluconeogenesis. Diabetes 61: 513‐523, 2012.
 284.Wong RH, Chang I, Hudak CS, Hyun S, Kwan HY, Sul HS. A role of DNA‐PK for the metabolic gene regulation in response to insulin. Cell 136: 1056‐1072, 2009.
 285.Wu JW, Wang SP, Casavant S, Moreau A, Yang GS, Mitchell GA. Fasting Energy Homeostasis in Mice with Adipose Deficiency of Desnutrin/Adipose Triglyceride Lipase. Endocrinology 153: 2198‐2207, 2012.
 286.Wu Z, Jiao P, Huang X, Feng B, Feng Y, Yang S, Hwang P, Du J, Nie Y, Xiao G, Xu H. MAPK phosphatase‐3 promotes hepatic gluconeogenesis through dephosphorylation of forkhead box O1 in mice. J Clin Invest 120: 3901‐3911, 2010.
 287.Xi L, Xiao C, Bandsma RH, Naples M, Adeli K, Lewis GF. C‐reactive protein impairs hepatic insulin sensitivity and insulin signaling in rats: Role of mitogen‐activated protein kinases. Hepatology 53: 127‐135, 2011.
 288.Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat‐derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest 112: 91‐100, 2003.
 289.Xu E, Charbonneau A, Rolland Y, Bellmann K, Pao L, Siminovitch KA, Neel BG, Beauchemin N, Marette A. Hepatocyte‐specific Ptpn6 deletion protects from obesity‐linked hepatic insulin resistance. Diabetes 61: 1949‐1958, 2012.
 290.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.
 291.Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty‐acid oxidation by activating AMP‐activated protein kinase. Nat Med 8: 1288‐1295, 2002.
 292.Yang X, Lu X, Lombes M, Rha GB, Chi YI, Guerin TM, Smart EJ, Liu J. The G(0)/G(1) switch gene 2 regulates adipose lipolysis through association with adipose triglyceride lipase. Cell Metab 11: 194‐205, 2010.
 293.Yecies JL, Zhang HH, Menon S, Liu S, Yecies D, Lipovsky AI, Gorgun C, Kwiatkowski DJ, Hotamisligil GS, Lee CH, Manning BD. Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1‐dependent and independent pathways. Cell Metab 14: 21‐32, 2011.
 294.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.
 295.Young SG, Zechner R. Biochemistry and pathophysiology of intravascular and intracellular lipolysis. Genes Dev 27: 459‐484, 2013.
 296.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.
 297.Zhang EE, Liu Y, Dentin R, Pongsawakul PY, Liu AC, Hirota T, Nusinow DA, Sun X, Landais S, Kodama Y, Brenner DA, Montminy M, Kay SA. Cryptochrome mediates circadian regulation of cAMP signaling and hepatic gluconeogenesis. Nat Med 16: 1152‐1156, 2010.
 298.Zhang K, Li L, Qi Y, Zhu X, Gan B, DePinho RA, Averitt T, Guo S. Hepatic suppression of Foxo1 and Foxo3 causes hypoglycemia and hyperlipidemia in mice. Endocrinology 153: 631‐646, 2012.
 299.Zhang T, Wang S, Lin Y, Xu W, Ye D, Xiong Y, Zhao S, Guan KL. Acetylation negatively regulates glycogen phosphorylase by recruiting protein phosphatase 1. Cell Metab 15: 75‐87, 2012.
 300.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.
 301.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.
 302.Zhao LF, Iwasaki Y, Nishiyama M, Taguchi T, Tsugita M, Okazaki M, Nakayama S, Kambayashi M, Fujimoto S, Hashimoto K, Murao K, Terada Y. Liver X receptor alpha is involved in the transcriptional regulation of the 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase gene. Diabetes 61: 1062‐1071, 2012.
 303.Zhao S, Xu W, Jiang W, Yu W, Lin Y, Zhang T, Yao J, Zhou L, Zeng Y, Li H, Li Y, Shi J, An W, Hancock SM, He F, Qin L, Chin J, Yang P, Chen X, Lei Q, Xiong Y, Guan KL. Regulation of cellular metabolism by protein lysine acetylation. Science 327: 1000‐1004, 2010.
 304.Zhao W, Kruse JP, Tang Y, Jung SY, Qin J, Gu W. Negative regulation of the deacetylase SIRT1 by DBC1. Nature 451: 587‐590, 2008.
 305.Zhou J, Zhai Y, Mu Y, Gong H, Uppal H, Toma D, Ren S, Evans RM, Xie W. A novel pregnane X receptor‐mediated and sterol regulatory element‐binding protein‐independent lipogenic pathway. J Biol Chem 281: 15013‐15020, 2006.
 306.Zhou XY, Shibusawa N, Naik K, Porras D, Temple K, Ou H, Kaihara K, Roe MW, Brady MJ, Wondisford FE. Insulin regulation of hepatic gluconeogenesis through phosphorylation of CREB‐binding protein. Nat Med 10: 633‐637, 2004.
 307.Zhou Y, Lee J, Reno CM, Sun C, Park SW, Chung J, Fisher SJ, White MF, Biddinger SB, Ozcan U. Regulation of glucose homeostasis through a XBP‐1‐FoxO1 interaction. Nat Med 17: 356‐365, 2011.

Related Articles:

Regulation of Gluconeogenesis in Liver
Regulation of Ketogenesis in Liver
Circadian Rhythms in Liver Physiology and Liver Diseases
Top cited articles of 2017

Contact Editor

Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite

Liangyou Rui. Energy Metabolism in the Liver. Compr Physiol 2014, 4: 177-197. doi: 10.1002/cphy.c130024