Nonalcoholic fatty liver disease, hepatic insulin resistance, and type 2 Diabetes

Hepatology

Volumn 59, Issue 2, 2014, Pages 713-723

  Birkenfeld, Andreas L ^a,b   Shulman, Gerald I ^b,c  

^a CHARITÉ UNIVERSITÄTSMEDIZIN BERLIN   (Germany)

^b YALE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^c Capital Region   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

APOLIPOPROTEIN C3; CERAMIDE; DIACYLGLYCEROL; INSULIN; LIPID; PERILIPIN; PROTEIN KINASE C EPSILON;

ARTICLE; CALORIC INTAKE; ENDOPLASMIC RETICULUM STRESS; FATTY LIVER; GENETICS; HEPATIC INSULIN RESISTANCE; HUMAN; INNATE IMMUNITY; INSULIN RESISTANCE; LIPID LIVER LEVEL; LIPID STORAGE; LIPIDOSIS; LIPODYSTROPHY; LIVER DISEASE; MUTATION; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; OBESITY; PATHOGENESIS; PRIORITY JOURNAL; SIGNAL TRANSDUCTION;

ANIMALS; DIABETES MELLITUS, TYPE 2; DIGLYCERIDES; DISEASE MODELS, ANIMAL; FATTY LIVER; HUMANS; INSULIN RESISTANCE; LIPID METABOLISM; LIVER; PROTEIN KINASE C-EPSILON;

EID: 84884860377     PISSN: 02709139     EISSN: 15273350     Source Type: Journal    
DOI: 10.1002/hep.26672     Document Type: Article

References (107)

1. World Health Organization. Obesity and Overweight Fact Sheet No. 311, 2012. Geneva: World Health Organization.
2. Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011;332:1519-1523.
3. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology 2010;51:679-689.
4. Stefan N, Haring HU. The metabolically benign and malignant fatty liver. Diabetes 2011;60:2011-2017.
5. Jornayvaz FR, Shulman GI. Diacylglycerol activation of protein kinase Cepsilon and hepatic insulin resistance. Cell Metab 2012;15:574-584.
6. Cusi K. Role of obesity and lipotoxicity in the development of nonalcoholic steatohepatitis: pathophysiology and clinical implications. Gastroenterology 2012;142:711-725.e6.
7. Alves TC, Befroy DE, Kibbey RG, Kahn M, Codella R, Carvalho RA, et al. Regulation of hepatic fat and glucose oxidation in rats with lipid-induced hepatic insulin resistance. Hepatology 2011;53:1175-1181.
8. Samuel VT, Petersen KF, Shulman GI. Lipid-induced insulin resistance: unravelling the mechanism. Lancet 2010;375:2267-2277.
9. Shulman GI. Cellular mechanisms of insulin resistance. J Clin Invest 2000;106:171-176.
10. Cusi K. Nonalcoholic fatty liver disease in type 2 diabetes mellitus. Curr Opin Endocrinol Diabetes Obes 2009;16:141-149.
11. Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, et al. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999;42:113-116.
12. Stefan N, Kantartzis K, Haring HU. Causes and metabolic consequences of fatty liver. Endocr Rev 2008;29:939-960.
13. Dresner A, Laurent D, Marcucci M, Griffin ME, Dufour S, Cline GW, et al. Effects of free fatty acids on glucose transport and IRS-1-associated phosphatidylinositol 3-kinase activity. J Clin Invest 1999;103:253-259.
14. Itani SI, Ruderman NB, Schmieder F, Boden G. Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkappaB-alpha. Diabetes 2002;51:2005-2011.
15. Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, et al. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proc Natl Acad Sci U S A 2011;108:16381-16385.
16. Magkos F, Su X, Bradley D, Fabbrini E, Conte C, Eagon JC, et al. Intrahepatic diacylglycerol content is associated with hepatic insulin resistance in obese subjects. Gastroenterology 2012;142:1444-1446.e2.
17. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, et al. Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. J Biol Chem 2004;279:32345-32353.
18. Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, et al. Inhibition of protein kinase Cepsilon prevents hepatic insulin resistance in nonalcoholic fatty liver disease. J Clin Invest 2007;117:739-745.
19. Frangioudakis G, Burchfield JG, Narasimhan S, Cooney GJ, Leitges M, Biden TJ, Schmitz-Peiffer C. Diverse roles for protein kinase C delta and protein kinase C epsilon in the generation of high-fat-diet-induced glucose intolerance in mice: regulation of lipogenesis by protein kinase C delta. Diabetologia 2009;52:2616-2620.
20. Neschen S, Morino K, Hammond LE, Zhang D, Liu ZX, Romanelli AJ, et al. Prevention of hepatic steatosis and hepatic insulin resistance in mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase 1 knockout mice. Cell Metab 2005;2:55-65.
21. Stone SJ, Levin MC, Zhou P, Han J, Walther TC, Farese RV, Jr. The endoplasmic reticulum enzyme DGAT2 is found in mitochondria-associated membranes and has a mitochondrial targeting signal that promotes its association with mitochondria. J Biol Chem 2009;284:5352-5361.
22. Jornayvaz FR, Birkenfeld AL, Jurczak MJ, Kanda S, Guigni BA, Jiang DC, et al. Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. Proc Natl Acad Sci U S A 2011;108:5748-5752.
23. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, et al. Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. J Biol Chem 2007;282:22678-22688.
24. Kaczocha M, Vivieca S, Sun J, Glaser ST, Deutsch DG. Fatty acid-binding proteins transport N-acylethanolamines to nuclear receptors and are targets of endocannabinoid transport inhibitors. J Biol Chem 2012;287:3415-3424.
25. -/- mice. J Lipid Res 2012;53:744-754.
26. Liu J, Zhou L, Xiong K, Godlewski G, Mukhopadhyay B, Tam J, et al. Hepatic cannabinoid receptor-1 mediates diet-induced insulin resistance via inhibition of insulin signaling and clearance in mice. Gastroenterology 2012;142:1218-1228.e1.
27. Tam J, Cinar R, Liu J, Godlewski G, Wesley D, Jourdan T, et al. Peripheral cannabinoid-1 receptor inverse agonism reduces obesity by reversing leptin resistance. Cell Metab 2012;16:167-179.
28. Silvestri C, Di Marzo V. The endocannabinoid system in energy homeostasis and the etiopathology of metabolic disorders. Cell Metab 2013;17:475-490.
29. Chanda D, Kim YH, Kim DK, Lee MW, Lee SY, Park TS, et al. Activation of cannabinoid receptor type 1 (Cb1r) disrupts hepatic insulin receptor signaling via cyclic AMP-response element-binding protein H (Crebh)-mediated induction of Lipin1 gene. J Biol Chem 2012;287:38041-38049.
30. Jeong WI, Osei-Hyiaman D, Park O, Liu J, Batkai S, Mukhopadhyay P, et al. Paracrine activation of hepatic CB1 receptors by stellate cell-derived endocannabinoids mediates alcoholic fatty liver. Cell Metab 2008;7:227-235.
31. Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, et al. Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metab 2011;14:184-195.
32. Erion DM, Ignatova ID, Yonemitsu S, Nagai Y, Chatterjee P, Weismann D, et al. Prevention of hepatic steatosis and hepatic insulin resistance by knockdown of cAMP response element-binding protein. Cell Metab 2009;10:499-506.
33. Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D, et al. A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. Am J Physiol Endocrinol Metab 2010;299:E808-E815.
34. Lee HY, Birkenfeld AL, Jornayvaz FR, Jurczak MJ, Kanda S, Popov V, et al. Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance. Hepatology 2011;54:1650-1660.
35. Jurczak MJ, Lee HY, Birkenfeld AL, Jornayvaz FR, Frederick DW, Pongratz RL, et al. SGLT2 deletion improves glucose homeostasis and preserves pancreatic beta-cell function. Diabetes 2011;60:890-898.
36. Kumashiro N, Yoshimura T, Cantley JL, Majumdar SK, Guebre-Egziabher F, Kursawe R, et al. Role of patatin-like phospholipase domain-containing 3 on lipid-induced hepatic steatosis and insulin resistance in rats. Hepatology 2013;57:1763-1772.
37. Brown WH, Gillum MP, Lee HY, Camporez JP, Zhang XM, Jeong JK, et al. Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism. Proc Natl Acad Sci U S A 2012;109:14966-14971.
38. Kumashiro N, Beddow SA, Vatner DF, Majumdar SK, Cantley JL, Guebre-Egziabher F, et al. Targeting pyruvate carboxylase reduces gluconeogenesis and adiposity and improves insulin resistance. Diabetes 2013;62:2183-2194.
39. Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005-2023.
40. Hilden M, Christoffersen P, Juhl E, Dalgaard JB. Liver histology in a 'normal' population-examinations of 503 consecutive fatal traffic casualties. Scand J Gastroenterol 1977;12:593-597.
41. Gholam PM, Kotler DP, Flancbaum LJ. Liver pathology in morbidly obese patients undergoing Roux-en-Y gastric bypass surgery. Obes Surg 2002;12:49-51.
42. Haufe S, Engeli S, Kast P, Bohnke J, Utz W, Haas V, et al. Randomized comparison of reduced fat and reduced carbohydrate hypocaloric diets on intrahepatic fat in overweight and obese human subjects. Hepatology 2011;53:1504-1514.
43. Haufe S, Haas V, Utz W, Kast P, Bohnke J, Mähler A, et al. Long lasting improvements in liver fat and function despite body weight regain following a six months hypocaloric diet. Diabetes Care 2013 epub ahead of print.
44. Sunny NE, Parks EJ, Browning JD, Burgess SC. Excessive hepatic mitochondrial TCA cycle and gluconeogenesis in humans with nonalcoholic fatty liver disease. Cell Metab 2011;14:804-810.
45. Goldberg IJ, Eckel RH, Abumrad NA. Regulation of fatty acid uptake into tissues: lipoprotein lipase- and CD36-mediated pathways. J Lipid Res 2009;50(Suppl):S86-S90.
46. Sadur CN, Yost TJ, Eckel RH. Insulin responsiveness of adipose tissue lipoprotein lipase is delayed but preserved in obesity. J Clin Endocrinol Metab 1984;59:1176-1182.
47. Westerbacka J, Kolak M, Kiviluoto T, Arkkila P, Siren J, Hamsten A, et al. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 2007;56:2759-2765.
48. Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, et al. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008;294:G1281-G1287.
49. Fabbrini E, Magkos F, Mohammed BS, Pietka T, Abumrad NA, Patterson BW, et al. Intrahepatic fat, not visceral fat, is linked with metabolic complications of obesity. Proc Natl Acad Sci U S A 2009;106:15430-15435.
50. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, et al. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proc Natl Acad Sci U S A 2001;98:7522-7527.
51. Merkel M, Weinstock PH, Chajek-Shaul T, Radner H, Yin B, Breslow JL, Goldberg IJ. Lipoprotein lipase expression exclusively in liver. A mouse model for metabolism in the neonatal period and during cachexia. J Clin Invest 1998;102:893-901.
52. Koonen DP, Jacobs RL, Febbraio M, Young ME, Soltys CL, Ong H, et al. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 2007;56:2863-2871.
53. 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 2010;299:E384-E393.
54. Kim JK, Gavrilova O, Chen Y, Reitman ML, Shulman GI. Mechanism of insulin resistance in A-ZIP/F-1 fatless mice. J Biol Chem 2000;275:8456-8460.
55. Shimomura I, Hammer RE, Ikemoto S, Brown MS, Goldstein JL. Leptin reverses insulin resistance and diabetes mellitus in mice with congenital lipodystrophy. Nature 1999;401:73-76.
56. Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, et al. Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. J Clin Invest 2002;109:1345-1350.
57. Schupp M, Lazar MA. Endogenous ligands for nuclear receptors: digging deeper. J Biol Chem 2010;285:40409-40415.
58. Savage DB, Tan GD, Acerini CL, Jebb SA, Agostini M, Gurnell M, et al. Human metabolic syndrome resulting from dominant-negative mutations in the nuclear receptor peroxisome proliferator-activated receptor-gamma. Diabetes 2003;52:910-917.
59. Matsusue K, Haluzik M, Lambert G, Yim SH, Gavrilova O, Ward JM, et al. Liver-specific disruption of PPARgamma in leptin-deficient mice improves fatty liver but aggravates diabetic phenotypes. J Clin Invest 2003;111:737-747.
60. Gavrilova O, Haluzik M, Matsusue K, Cutson JJ, Johnson L, Dietz KR, et al. Liver peroxisome proliferator-activated receptor gamma contributes to hepatic steatosis, triglyceride clearance, and regulation of body fat mass. J Biol Chem 2003;278:34268-34276.
61. Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, et al. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes 2002;51:797-802.
62. Bajaj M, Baig R, Suraamornkul S, Hardies LJ, Coletta DK, Cline GW, et al. Effects of pioglitazone on intramyocellular fat metabolism in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2010;95:1916-1923.
63. Luedtke A, Boschmann M, Colpe C, Engeli S, Adams F, Birkenfeld AL, et al. Thiazolidinedione response in familial lipodystrophy patients with LMNA mutations: a case series. Horm Metab Res 2012;44:306-311.
64. Kim JK, Michael MD, Previs SF, Peroni OD, Mauvais-Jarvis F, Neschen S, et al. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J Clin Invest 2000;105:1791-1797.
65. Kotani K, Peroni OD, Minokoshi Y, Boss O, Kahn BB. GLUT4 glucose transporter deficiency increases hepatic lipid production and peripheral lipid utilization. J Clin Invest 2004;114:1666-1675.
66. Petersen KF, Dufour S, Savage DB, Bilz S, Solomon G, Yonemitsu S, et al. The role of skeletal muscle insulin resistance in the pathogenesis of the metabolic syndrome. Proc Natl Acad Sci U S A 2007;104:12587-12594.
67. Rabol R, Petersen KF, Dufour S, Flannery C, Shulman GI. Reversal of muscle insulin resistance with exercise reduces postprandial hepatic de novo lipogenesis in insulin resistant individuals. Proc Natl Acad Sci U S A 2011;108:13705-13709.
68. Haufe S, Engeli S, Budziarek P, Utz W, Schulz-Menger J, Hermsdorf M, et al. Cardiorespiratory fitness and insulin sensitivity in overweight or obese subjects may be linked through intrahepatic lipid content. Diabetes 2010;59:1640-1647.
69. Sullivan S, Kirk EP, Mittendorfer B, Patterson BW, Klein S. Randomized trial of exercise effect on intrahepatic triglyceride content and lipid kinetics in nonalcoholic fatty liver disease. Hepatology 2012;55:1738-1745.
70. Li WW, Dammerman MM, Smith JD, Metzger S, Breslow JL, Leff T. Common genetic variation in the promoter of the human apo CIII gene abolishes regulation by insulin and may contribute to hypertriglyceridemia. J Clin Invest 1995;96:2601-2605.
71. Petersen KF, Dufour S, Hariri A, Nelson-Williams C, Foo JN, Zhang XM, et al. Apolipoprotein C3 gene variants in nonalcoholic fatty liver disease. N Engl J Med 2010;362:1082-1089.
72. Valenti L, Nobili V, Al-Serri A, Rametta R, Leathart JB, Zappa MA, et al. The APOC3 T-455C and C-482T promoter region polymorphisms are not associated with the severity of liver damage independently of PNPLA3 I148M genotype in patients with nonalcoholic fatty liver. J Hepatol 2011;55:1409-1414.
73. Hyysalo J, Stojkovic I, Kotronen A, Hakkarainen A, Sevastianova K, Makkonen J, et al. Genetic variation in PNPLA3 but not APOC3 influences liver fat in non-alcoholic fatty liver disease. J Gastroenterol Hepatol 2012;27:951-956.
74. Coban N, Onat A, Guclu-Geyik F, Komurcu-Bayrak E, Sansoy V, Hergenc G, et al. Gender- and obesity-specific effect of apolipoprotein C3 gene (APOC3) -482C>T polymorphism on triglyceride concentration in Turkish adults. Clin Chem Lab Med 2012;50:285-292.
75. Peter A, Kantartzis K, Machicao F, Machann J, Wagner S, Templin S, et al. Visceral obesity modulates the impact of apolipoprotein C3 gene variants on liver fat content. Int J Obes (Lond) 2012;36:774-782.
76. Gandotra S, Lim K, Girousse A, Saudek V, O'Rahilly S, Savage DB. Human frame shift mutations affecting the carboxyl terminus of perilipin increase lipolysis by failing to sequester the adipose triglyceride lipase (ATGL) coactivator AB-hydrolase-containing 5 (ABHD5). J Biol Chem 2011;286:34998-35006.
77. Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, et al. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med 2011;364:740-748.
78. Rohm M, Sommerfeld A, Strzoda D, Jones A, Sijmonsma TP, Rudofsky G, et al. Transcriptional cofactor TBLR1 controls lipid mobilization in white adipose tissue. Cell Metab 2013;17:575-585.
79. Liska D, Dufour S, Zern TL, Taksali S, Cali AM, Dziura J, et al. Interethnic differences in muscle, liver and abdominal fat partitioning in obese adolescents. PLoS One 2007;2:e569.
80. Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008;40:1461-1465.
81. Kantartzis K, Peter A, Machicao F, Machann J, Wagner S, Konigsrainer I, et al. Dissociation between fatty liver and insulin resistance in humans carrying a variant of the patatin-like phospholipase 3 gene. Diabetes 2009;58:2616-2623.
82. Jenkins CM, Mancuso DJ, Yan W, Sims HF, Gibson B, Gross RW. Identification, cloning, expression, and purification of three novel human calcium-independent phospholipase A2 family members possessing triacylglycerol lipase and acylglycerol transacylase activities. J Biol Chem 2004;279:48968-48975.
83. He S, McPhaul C, Li JZ, Garuti R, Kinch L, Grishin NV, et al. A sequence variation (I148M) in PNPLA3 associated with nonalcoholic fatty liver disease disrupts triglyceride hydrolysis. J Biol Chem 2010;285:6706-6715.
84. Qiao A, Liang J, Ke Y, Li C, Cui Y, Shen L, et al. Mouse patatin-like phospholipase domain-containing 3 influences systemic lipid and glucose homeostasis. Hepatology 2011;54:509-521.
85. Basantani MK, Sitnick MT, Cai L, Brenner DS, Gardner NP, Li JZ, et al. Pnpla3/Adiponutrin deficiency in mice does not contribute to fatty liver disease or metabolic syndrome. J Lipid Res 2011;52:318-329.
86. Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, et al. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004;306:1383-1386.
87. Villena JA, Roy S, Sarkadi-Nagy E, Kim KH, Sul HS. Desnutrin, an adipocyte gene encoding a novel patatin domain-containing protein, is induced by fasting and glucocorticoids: ectopic expression of desnutrin increases triglyceride hydrolysis. J Biol Chem 2004;279:47066-47075.
88. Haemmerle G, Lass A, Zimmermann R, Gorkiewicz G, Meyer C, Rozman J, et al. Defective lipolysis and altered energy metabolism in mice lacking adipose triglyceride lipase. Science 2006;312:734-737.
89. Wu JW, Wang SP, Alvarez F, Casavant S, Gauthier N, Abed L, et al. Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology 2011;54:122-132.
90. Turpin SM, Hoy AJ, Brown RD, Rudaz CG, Honeyman J, Matzaris M, Watt MJ. Adipose triacylglycerol lipase is a major regulator of hepatic lipid metabolism but not insulin sensitivity in mice. Diabetologia 2011;54:146-156.
91. Cantley JL, Yoshimura T, Camporez JP, Zhang D, Jornayvaz FR, Kumashiro N, et al. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proc Natl Acad Sci U S A 2013;110:1869-1874.
92. Chavez JA, Summers SA. A ceramide-centric view of insulin resistance. Cell Metab 2012;15:585-594.
93. Galbo T, Perry RJ, Jurczak MJ, Camporez JP, Alves TC, Kahn M, et al. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo. Proc Natl Acad Sci U S A 2013;110:12780-12785.
94. Fu S, Watkins SM, Hotamisligil GS. The role of endoplasmic reticulum in hepatic lipid homeostasis and stress signaling. Cell Metab 2012;15:623-634.
95. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science 2011;334:1081-1086.
96. Jurczak MJ, Lee AH, Jornayvaz FR, Lee HY, Birkenfeld AL, Guigni BA, et al. Dissociation of inositol-requiring enzyme (IRE1alpha)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-box-binding protein-1 (XBP1) knock-out mice. J Biol Chem 2012;287:2558-2567.
97. Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, et al. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009;119:1201-1215.
98. 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 2008;7:520-532.
99. Birkenfeld AL, Lee HY, Majumdar S, Jurczak MJ, Camporez JP, Jornayvaz FR, et al. Influence of the hepatic eukaryotic initiation factor 2alpha (eIF2alpha) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism. J Biol Chem 2011;286:36163-36170.
100. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87-91.
101. Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW, Jr. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003;112:1796-1808.
102. Kanda H, Tateya S, Tamori Y, Kotani K, Hiasa K, Kitazawa R, et al. MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity. J Clin Invest 2006;116:1494-1505.
103. Sabio G, Das M, Mora A, Zhang Z, Jun JY, Ko HJ, et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 2008;322:1539-1543.
104. Henkel J, Neuschafer-Rube F, Pathe-Neuschafer-Rube A, Puschel GP. Aggravation by prostaglandin E2 of interleukin-6-dependent insulin resistance in hepatocytes. Hepatology 2009;50:781-790.
105. Sabio G, Cavanagh-Kyros J, Ko HJ, Jung DY, Gray S, Jun JY, et al. Prevention of steatosis by hepatic JNK1. Cell Metab 2009;10:491-498.
106. Flach RJ, Qin H, Zhang L, Bennett AM. Loss of mitogen-activated protein kinase phosphatase-1 protects from hepatic steatosis by repression of cell death-inducing DNA fragmentation factor A (DFFA)-like effector C (CIDEC)/fat-specific protein 27. J Biol Chem 2011;286:22195-22202.
107. Copps KD, Hancer NJ, Opare-Ado L, Qiu W, Walsh C, White MF. Irs1 serine 307 promotes insulin sensitivity in mice. Cell Metab 2010;11:84-92.