Inflammation as a potential link between nonalcoholic fatty liver disease and insulin resistance

Journal of Endocrinology

Volumn 218, Issue 3, 2013, Pages

  Asrih, Mohamed ^a   Jornayvaz, François R ^a  

^a GENEVA UNIVERSITY HOSPITALS   (Switzerland)

Author keywords

Inflammatory diseases; Insulin resistance; Lipid; Liver; Obesity

Indexed keywords

ADIPOCYTOKINE; ADIPONECTIN; CERAMIDE; CYTOKINE; DIACYLGLYCEROL; INTERLEUKIN 10; INTERLEUKIN 6; LIPID; TUMOR NECROSIS FACTOR ALPHA;

BIOACCUMULATION; DEVELOPED COUNTRY; DISEASE ASSOCIATION; ENERGY BALANCE; FATTY LIVER; HUMAN; IMMUNE RESPONSE; INFLAMMATION; INSULIN RESISTANCE; METABOLIC SYNDROME X; NON INSULIN DEPENDENT DIABETES MELLITUS; NONALCOHOLIC FATTY LIVER; NONHUMAN; PATHOPHYSIOLOGY; PRIORITY JOURNAL; REVIEW; RISK FACTOR; WHITE ADIPOSE TISSUE;

INFLAMMATORY DISEASES; INSULIN RESISTANCE; LIPID; LIVER; OBESITY;

ADIPOKINES; ANIMALS; CYTOKINES; FATTY LIVER; HUMANS; INSULIN RESISTANCE; LIVER;

EID: 84884176199     PISSN: 00220795     EISSN: 14796805     Source Type: Journal    
DOI: 10.1530/JOE-13-0201     Document Type: Review

References (116)

1. Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, & Angulo P 2005 The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 129 113-121. (doi:10.1053/j.gastro.2005.04.014)
2. Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr et al. 2009 Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120 1640-1645. (doi:10.1161/CIRCULATIONAHA.109.192644)
3. Alfrey EJ, Most D,Wang X, Lee LK, Holm B, Krieger NR, Sibley RK, Huie P, & Dafoe DC 1995 Interferon-g and interleukin-10 messenger RNA are up-regulated after orthotopic liver transplantation in tolerant rats: evidence for cytokine-mediated immune dysregulation. Surgery 118 399-404 (discussion 404-405). (doi:10.1016/S0039-6060(05)80351-4)
4. Amarapurkar DN, Hashimoto E, Lesmana LA, Sollano JD, Chen PJ, Goh KL, & Asia-Pacific Working Party on N 2007 How common is nonalcoholic fatty liver disease in the Asia-Pacific region and are there local differences?. Journal of Gastroenterology and Hepatology 22 788-793. (doi:10.1111/j.1440-1746.2007.05042.x)
5. An J, Muoio DM, Shiota M, Fujimoto Y, Cline GW, Shulman GI, Koves TR, Stevens R, Millington D, & Newgard CB 2004 Hepatic expression of malonyl-CoA decarboxylase reverses muscle, liver and whole-animal insulin resistance. Nature Medicine 10 268-274. (doi:10.1038/nm995)
6. Apovian CM, Bigornia S, Mott M, Meyers MR, Ulloor J, Gagua M, McDonnell M, Hess D, Joseph L, & Gokce N 2008 Adipose macrophage infiltration is associated with insulin resistance and vascular endothelial dysfunction in obese subjects. Arteriosclerosis, Thrombosis, and Vascular Biology 28 1654-1659. (doi:10.1161/ATVBAHA.108.170316)
7. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K et al. 1999 Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochemical and Biophysical Research Communications 257 79-83. (doi:10.1006/bbrc. 1999.0255)
8. Arner P 2003 The adipocyte in insulin resistance: key molecules and the impact of the thiazolidinediones. Trends in Endocrinology and Metabolism 14 137-145. (doi:10.1016/S1043-2760(03)00024-9)
9. Ayala JE, Samuel VT, Morton GJ, Obici S, Croniger CM, Shulman GI, Wasserman DH, McGuinness OP, & Consortium NIHMMPC 2010 Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Disease Models, & Mechanisms 3 525-534. (doi:10.1242/dmm.006239)
10. Balent B, Goswami G, Goodloe G, Rogatsky E, Rauta O, Nezami R, Mints L, Angeletti RH, & Stein DT 2002 Acute elevation of NEFA causes hyperinsulinemia without effect on insulin secretion rate in healthy human subjects. Annals of the New York Academy of Sciences 967 535-543. (doi:10.1111/j.1749-6632.2002.tb04313.x)
11. Bandyopadhyay GK, Yu JG, Ofrecio J, & Olefsky JM 2005 Increased p85/55/50 expression and decreased phosphotidylinositol 3-kinase activity in insulin-resistant human skeletal muscle. Diabetes 54 2351-2359. (doi:10.2337/diabetes.54.8.2351)
12. Bastard JP, Maachi M, Van Nhieu JT, Jardel C, Bruckert E, Grimaldi A, Robert JJ, Capeau J, & Hainque B 2002 Adipose tissue IL-6 content correlates with resistance to insulin activation of glucose uptake both in vivo and in vitro. Journal of Clinical Endocrinology and Metabolism 87 2084-2089. (doi:10.1210/jc.87.5.2084)
13. Begriche K, Igoudjil A, Pessayre D, & Fromenty B 2006 Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion 6 1-28. (doi:10.1016/j.mito.2005.10.004)
14. Bikman BT, & Summers SA 2011 Ceramides as modulators of cellular and whole-body metabolism. Journal of Clinical Investigation 121 4222-4230. (doi:10.1172/JCI57144)
15. Birkenfeld AL, Lee HY, Guebre-Egziabher F, Alves TC, Jurczak MJ, Jornayvaz FR, Zhang D, Hsiao JJ, Martin-Montalvo A, Fischer-Rosinsky A et al. 2011a Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice. Cell Metabolism 14 184-195. (doi:10.1016/j.cmet. 2011.06.019)
16. Birkenfeld AL, Lee HY, Majumdar S, JurczakMJ, Camporez JP, Jornayvaz FR, Frederick DW, Guigni B, Kahn M, Zhang D et al. 2011b Influence of the hepatic eukaryotic initiation factor 2a (eIF2a) endoplasmic reticulum (ER) stress response pathway on insulin-mediated ER stress and hepatic and peripheral glucose metabolism. Journal of Biological Chemistry 286 36163-36170. (doi:10.1074/jbc.M111.228817)
17. Boden G, & Shulman GI 2002 Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and b-cell dysfunction. European Journal of Clinical Investigation 32(Suppl 3) 14-23. (doi:10.1046/j.1365-2362.32.s3.3.x)
18. den Boer MA, Voshol PJ, Schroder-van der Elst JP, Korsheninnikova E, Ouwens DM, Kuipers F, Havekes LM, & Romijn JA 2006 Endogenous interleukin-10 protects against hepatic steatosis but does not improve insulin sensitivity during high-fat feeding in mice. Endocrinology 147 4553-4558. (doi:10.1210/en.2006-0417)
19. Brown MS, & Goldstein JL 2008 Selective versus total insulin resistance: a pathogenic paradox. Cell Metabolism 7 95-96. (doi:10.1016/j.cmet. 2007.12.019)
20. Bruun JM, Lihn AS, Verdich C, Pedersen SB, Toubro S, Astrup A, & Richelsen B 2003 Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. American Journal of Physiology. Endocrinology and Metabolism 285 E527-E533.
21. Bugianesi E, Gastaldelli A, Vanni E, Gambino R, Cassader M, Baldi S, Ponti V, Pagano G, Ferrannini E, & Rizzetto M 2005a Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms. Diabetologia 48 634-642. (doi:10.1007/ s00125-005-1682-x)
22. Bugianesi E, McCullough AJ, & Marchesini G 2005b Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 42 987-1000. (doi:10.1002/hep.21920)
23. Camporez JP, Jornayvaz FR, Lee HY, Kanda S, Guigni BA, Kahn M, Samuel VT, Carvalho CR, Petersen KF, Jurczak MJ et al. 2013 Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance. Endocrinology 154 1021-1028. (doi:10.1210/en.2012-1989)
24. Cantley JL, Yoshimura T, Camporez JP, Zhang D, Jornayvaz FR, Kumashiro N, Guebre-Egziabher F, Jurczak MJ, Kahn M, Guigni BA et al. 2013 CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. PNAS 110 1869-1874. (doi:10.1073/pnas.1219456110)
25. Carpentier A, Mittelman SD, Bergman RN, Giacca A, & Lewis GF 2000 Prolonged elevation of plasma free fatty acids impairs pancreatic b-cell function in obese nondiabetic humans but not in individuals with type 2 diabetes. Diabetes 49 399-408. (doi:10.2337/diabetes.49.3.399)
26. Chatterjee S 1993 Neutral sphingomyelinase. Advances in Lipid Research 26 25-48.
27. Choi SS, & Diehl AM 2008 Hepatic triglyceride synthesis and nonalcoholic fatty liver disease. Current Opinion in Lipidology 19 295-300. (doi:10.1197/MOL.0b013e3282ff5e55)
28. Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S et al. 2007 Suppression of diacylglycerol acyltransferase-2 (DGAT2), but not DGAT1, with antisense oligonucleotides reverses diet-induced hepatic steatosis and insulin resistance. Journal of Biological Chemistry 282 22678-22688. (doi:10.1074/jbc.M704213200)
29. Cintra DE, Pauli JR, Araujo EP, Moraes JC, de Souza CT, Milanski M, Morari J, Gambero A, Saad MJ, & Velloso LA 2008 Interleukin-10 is a protective factor against diet-induced insulin resistance in liver. Journal of Hepatology 48 628-637. (doi:10.1016/j.jhep.2007.12.017)
30. Cleasby ME, Reinten TA, Cooney GJ, James DE, & Kraegen EW 2007 Functional studies of Akt isoform specificity in skeletal muscle in vivo; maintained insulin sensitivity despite reduced insulin receptor substrate-1 expression. Molecular Endocrinology 21 215-228. (doi:10.1210/me.2006-0154)
31. Colicchio P, Tarantino G, del Genio F, Sorrentino P, Saldalamacchia G, Finelli C, Conca P, Contaldo F&Pasanisi F 2005 Non-alcoholic fatty liver disease in young adult severely obese non-diabetic patients in South Italy. Annals of Nutrition, & Metabolism 49 289-295. (doi:10.1159/ 000087295)
32. Cressman DE, Greenbaum LE, DeAngelis RA, Ciliberto G, Furth EE, Poli V, & Taub R 1996 Liver failure and defective hepatocyte regeneration in interleukin-6-deficient mice. Science 274 1379-1383. (doi:10.1126/ science.274.5291.1379)
33. Das K, Das K, Mukherjee PS, Ghosh A, Ghosh S, Mridha AR, Dhibar T, Bhattacharya B, Bhattacharya D, Manna B et al. 2010 Nonobese population in a developing country has a high prevalence of nonalcoholic fatty liver and significant liver disease. Hepatology 51 1593-1602. (doi:10.1002/hep.23567)
34. Day CP, & James OF 1998 Steatohepatitis: a tale of two "hits"? Gastroenterology 114 842-845. (doi:10.1016/S0016-5085(98)70599-2)
35. Diehl AM, Li ZP, Lin HZ, & Yang SQ 2005 Cytokines and the pathogenesis of non-alcoholic steatohepatitis. Gut 54 303-306. (doi:10.1136/gut.2003. 024935)
36. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD, & Parks EJ 2005 Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. Journal of Clinical Investigation 115 1343-1351. (doi:10.1172/JCI23621)
37. Eckel RH, Grundy SM, & Zimmet PZ 2005 The metabolic syndrome. Lancet 365 1415-1428. (doi:10.1016/S0140-6736(05)66378-7)
38. El-Assal O, Hong F, Kim WH, Radaeva S, & Gao B 2004 IL-6-deficient mice are susceptible to ethanol-induced hepatic steatosis: IL-6 protects against ethanol-induced oxidative stress and mitochondrial permeability transition in the liver. Cellular, & Molecular Immunology 1 205-211.
39. Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke J, Mohlig M, Pfeiffer AF, Luft FC, & Sharma AM 2003 Association between adiponectin and mediators of inflammation in obese women. Diabetes 52 942-947. (doi:10.2337/diabetes.52.4.942)
40. Flegal KM, Graubard BI, Williamson DF, & Gail MH 2007 Cause-specific excess deaths associated with underweight, overweight, and obesity. Journal of the American Medical Association 298 2028-2037. (doi:10.1001/jama.298.17.2028)
41. Freedman DS 2011 Obesity - United States, 1988-2008. MMWR Surveillance Summaries 60(Suppl) 73-77.
42. Gariani K, Philippe J, & Jornayvaz FR 2013 Non-alcoholic fatty liver disease and insulin resistance: from bench to bedside. Diabetes, &Metabolism 39 16-26. (doi:10.1016/j.diabet.2012.11.002)
43. Goldfine AB, Fonseca V, Jablonski KA, Pyle L, Staten MA, Shoelson SE et al. 2010 The effects of salsalate on glycemic control in patients with type 2 diabetes: a randomized trial. Annals of internal medicine 152(6) 346-357.
44. Griffin ME, Marcucci MJ, Cline GW, Bell K, Barucci N, Lee D, Goodyear LJ, Kraegen EW, White MF, & Shulman GI 1999 Free fatty acid-induced insulin resistance is associated with activation of protein kinase C theta and alterations in the insulin signaling cascade. Diabetes 48 1270-1274. (doi:10.2337/diabetes.48.6.1270)
45. Gwechenberger M, Mendoza LH, Youker KA, Frangogiannis NG, Smith CW, Michael LH&EntmanML 1999 Cardiac myocytes produce interleukin-6 in culture and in viable border zone of reperfused infarctions. Circulation 99 546-551. (doi:10.1161/01.CIR.99.4.546)
46. Halberg N, Wernstedt-Asterholm I, & Scherer PE 2008 The adipocyte as an endocrine cell. Endocrinology and Metabolism Clinics of North America 37 753-768 (x-xi). (doi:10.1016/j.ecl.2008.07.002)
47. Hoehn KL, Hohnen-Behrens C, Cederberg A, Wu LE, Turner N, Yuasa T, Ebina Y, & James DE 2008 IRS1-independent defects define major nodes of insulin resistance. Cell Metabolism 7 421-433. (doi:10.1016/j.cmet. 2008.04.005)
48. Holland WL, Miller RA, Wang ZV, Sun K, Barth BM, Bui HH, Davis KE, Bikman BT, Halberg N, Rutkowski JM et al. 2011 Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nature Medicine 17 55-63. (doi:10.1038/nm.2277)
49. Hotamisligil GS 2003 Inflammatory pathways and insulin action. International Journal of Obesity and Related Metabolic Disorders 27(Suppl 3) S53-S55. (doi:10.1038/sj.ijo.0802502)
50. Hotamisligil GS, Shargill NS, & Spiegelman BM 1993 Adipose expression of tumor necrosis factor-a: direct role in obesity-linked insulin resistance. Science 259 87-91. (doi:10.1126/science.7678183)
51. Hotamisligil GS, Arner P, Caro JF, Atkinson RL, & Spiegelman BM 1995 Increased adipose tissue expression of tumor necrosis factor-a in human obesity and insulin resistance. Journal of Clinical Investigation 95 2419-2415. (doi:10.1172/JCI117936)
52. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K et al. 2000 Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arteriosclerosis, Thrombosis, and Vascular Biology 20 1595-1599. (doi:10.1161/01.ATV.20.6.1595)
53. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, & George J 2004 Beyond insulin resistance in NASH: TNF-a or adiponectin?. Hepatology 40 46-54. (doi:10.1002/hep.20280)
54. Itani SI, Ruderman NB, Schmieder F, & Boden G 2002 Lipid-induced insulin resistance in human muscle is associated with changes in diacylglycerol, protein kinase C, and IkB-a. Diabetes 51 2005-2011. (doi:10.2337/diabetes.51.7.2005)
55. Jornayvaz FR, & Shulman GI 2012 Diacylglycerol activation of protein kinase C3 and hepatic insulin resistance. Cell Metabolism 15 574-584. (doi:10.1016/j.cmet.2012.03.005)
56. Jornayvaz FR, Jurczak MJ, Lee HY, Birkenfeld AL, Frederick DW, Zhang D, Zhang XM, Samuel VT, & Shulman GI 2010 A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain. American Journal of Physiology. Endocrinology and Metabolism 299 E808-E815. (doi:10.1152/ajpendo. 00361.2010)
57. Jornayvaz FR, Birkenfeld AL, Jurczak MJ, Kanda S, Guigni BA, Jiang DC, Zhang D, Lee HY, Samuel VT, & Shulman GI 2011 Hepatic insulin resistance in mice with hepatic overexpression of diacylglycerol acyltransferase 2. PNAS 108 5748-5752. (doi:10.1073/pnas. 1103451108)
58. Jornayvaz FR, Lee HY, Jurczak MJ, Alves TC, Guebre-Egziabher F, Guigni BA, Zhang D, Samuel VT, Silva JE, & Shulman GI 2012 Thyroid hormone receptor-a gene knockout mice are protected from diet-induced hepatic insulin resistance. Endocrinology 153 583-591. (doi:10.1210/en.2011- 1793)
59. Jung SH, Park HS, Kim KS, Choi WH, Ahn CW, Kim BT, Kim SM, Lee SY, Ahn SM, Kim YK et al. 2008 Effect of weight loss on some serum cytokines in human obesity: increase in IL-10 after weight loss. Journal of Nutritional Biochemistry 19 371-375. (doi:10.1016/j.jnutbio. 2007.05.007)
60. Jurczak MJ, Lee AH, Jornayvaz FR, Lee HY, Birkenfeld AL, Guigni BA, Kahn M, Samuel VT, Glimcher LH, & Shulman GI 2012 Dissociation of inositol-requiring enzyme (IRE1a)-mediated c-Jun N-terminal kinase activation from hepatic insulin resistance in conditional X-boxbinding protein-1 (XBP1) knock-out mice. Journal of Biological Chemistry 287 2558-2567. (doi:10.1074/jbc.M111.316760)
61. Kern PA, Di Gregorio GB, Lu T, Rassouli N, & Ranganathan G 2003 Adiponectin expression from human adipose tissue: relation to obesity, insulin resistance, and tumor necrosis factor-a expression. Diabetes 52 1779-1785. (doi:10.2337/diabetes.52.7.1779)
62. Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ et al. 2001 Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. PNAS 98 7522-7527. (doi:10.1073/pnas.121164498)
63. Kishimoto T 2010 IL-6: from its discovery to clinical applications. International Immunology 22 347-352. (doi:10.1193/intimm/dxq030)
64. Kotronen A, Juurinen L, Tiikkainen M, Vehkavaara S, & Yki-Jarvinen H 2008 Increased liver fat, impaired insulin clearance, and hepatic and adipose tissue insulin resistance in type 2 diabetes. Gastroenterology 135 122-130. (doi:10.1053/j.gastro.2008.03.021)
65. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, Maeda K, Nagaretani H, Kishida K, Maeda N et al. 2004 Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation 119 2046-2049. (doi:10.1161/01.CIR.0000127953.98131.ED)
66. Lang CH, Dobrescu C, & Bagby GJ 1992 Tumor necrosis factor impairs insulin action on peripheral glucose disposal and hepatic glucose output. Endocrinology 130 43-52. (doi:10.1210/en.130.1.43)
67. Laplante M, & Sabatini D 2010 mTORC1 activates SREBP-1c and uncouples lipogenesis from gluconeogenesis. PNAS 107 3281-3282 (erratum: vol 107, pp 7617). (doi:10.1073/pnas.1000323107)
68. Lee YM, Sutedja DS,Wai CT, Dan YY, Aung MO, Zhou L, Cheng CL, Wee A, & Lim SG 2008 A randomized controlled pilot study of Pentoxifylline in patients with non-alcoholic steatohepatitis (NASH). Hepatology International 2 196-201. (doi:10.1007/s12072-008-9058-1)
69. Lee HY, Birkenfeld AL, Jornayvaz FR, Jurczak MJ, Kanda S, Popov V, Frederick DW, Zhang D, Guigni B, Bharadwaj KG et al. 2011 Apolipoprotein CIII overexpressing mice are predisposed to diet-induced hepatic steatosis and hepatic insulin resistance. Hepatology 54 1650-1660. (doi:10.1002/hep.24571)
70. Le Moine O, Marchant A, Durand F, Ickx B, Pradier O, Belghiti J, Abramowicz D, Gelin M, GoldmanM& Deviere J 1994 Systemic release of interleukin-10 during orthotopic liver transplantation. Hepatology 20 889-892. (doi:10.1002/hep.1840200417)
71. Lesmana CR, Hasan I, Budihusodo U, Gani RA, Krisnuhoni E, Akbar N, & Lesmana LA 2019 Diagnostic value of a group of biochemicalmarkers of liver fibrosis in patients with non-alcoholic steatohepatitis. Journal of Digestive Diseases 10 201-206. (doi:10.1111/j.1751-2980.2019.00386.x)
72. Lucero D, Zago V, Lopez GI, Graffigna M, Fainboim H, Miksztowicz V, Merono T, Belli S, Levalle O, Wikinski R et al. 2011 Pro-inflammatory and atherogenic circulating factors in non-alcoholic fatty liver disease associated to metabolic syndrome. Clinica Chimica Acta 412 143-147. (doi:10.1016/j.cca.2010.19.025)
73. Lumeng CN, & Saltiel AR 2011 Inflammatory links between obesity and metabolic disease. Journal of Clinical Investigation 121 2111-2117. (doi:10.1172/JCI57132)
74. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, McCullough AJ, Natale S, Forlani G, & Melchionda N 2001 Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes 50 1844-1850. (doi:10.2337/diabetes.50.8.1844)
75. Marra F, & Bertolani C 2019 Adipokines in liver diseases. Hepatology 50 957-969. (doi:10.1002/hep.23046)
76. Meyer SG, & de Groot H 2003 Cycloserine and threo-dihydrosphingosine inhibit TNF-a-induced cytotoxicity: evidence for the importance of de novo ceramide synthesis in TNF-a signaling. Biochimica et Biophysica Acta 1643 1-4. (doi:10.1016/j.bbamcr.2003.10.002)
77. Monetti M, Levin MC, Watt MJ, Sajan MP, Marmor S, Hubbard BK, Stevens RD, Bain JR, Newgard CB, Farese RV Sr et al. 2007 Dissociation of hepatic steatosis and insulin resistance inmice overexpressing DGAT in the liver. Cell Metabolism 6 69-78. (doi:10.1016/j.cmet.2007.05.005)
78. Moschen AR, Wieser V, & Tilg H 2012 Adiponectin: key player in the adipose tissue-liver crosstalk. Current Medicinal Chemistry 19 5467-5473. (doi:10.2174/192986712803833254)
79. Musso G, Cassader M, Rosina F, & Gambino R 2012 Impact of current treatments on liver disease, glucose metabolism and cardiovascular risk in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of randomised trials. Diabetologia 55 885-904. (doi:10.1007/s00125-011-2446-4)
80. Nadler ST, Stoehr JP, Rabaglia ME, Schueler KL, Birnbaum MJ, & Attie AD 2001 Normal Akt/PKB with reduced PI3K activation in insulin-resistant mice. American Journal of Physiology. Endocrinology and Metabolism 281 E1249-E1254.
81. Odegaard JI, & Chawla A 2013 Pleiotropic actions of insulin resistance and inflammation in metabolic homeostasis. Science 339 172-177. (doi:10.1126/science.1230721)
82. Ofei F, Hurel S, Newkirk J, Sopwith M, & Taylor R 1996 Effects of an engineered human anti-TNF-a antibody (CDP571) on insulin sensitivity and glycemic control in patients with NIDDM. Diabetes 45 881-885. (doi:10.2337/diabetes.45.7.881)
83. Park TS, Hu Y, Noh HL, Drosatos K, Okajima K, Buchanan J, Tuinei J, Homma S, Jiang XC, Abel ED et al. 2008 Ceramide is a cardiotoxin in lipotoxic cardiomyopathy. Journal of Lipid Research 49 2101-2112. (doi:10.1194/jlr.M800147-JLR200)
84. Petersen KF, & Shulman GI 2006 Etiology of insulin resistance. American Journal of Medicine 119 S10-S16. (doi:10.1016/j.amjmed.2006.01.019)
85. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, & Shulman GI 2005 Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes 54 603-608. (doi:10.2337/diabetes.54.3.603)
86. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, & Marchesini G 2010 A position statement on NAFLD/NASH based on the EASL 2019 special conference. Journal of Hepatology 53 372-384. (doi:10.1016/j.jhep.2010. 04.008)
87. Rodriguez A, Duran A, Selloum M, Champy MF, Diez-Guerra FJ, Flores JM, Serrano M, Auwerx J, Diaz-Meco MT, & Moscat J 2006 Mature-onset obesity and insulin resistance in mice deficient in the signaling adapter p62. Cell Metabolism 3 211-222. (doi:10.1016/j.cmet.2006.01.011)
88. Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, & Shulman GI 2004 Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. Journal of Biological Chemistry 279 32345-32353. (doi:10.1074/jbc.M313478200)
89. Savage DB, Choi CS, Samuel VT, Liu ZX, Zhang D, Wang A, Zhang XM, Cline GW, Yu XX, Geisler JG et al. 2006 Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2. Journal of Clinical Investigation 116 817-824. (doi:10.1172/JCI27300)
90. Schenk S, Saberi M, & Olefsky JM 2008 Insulin sensitivity: modulation by nutrients and inflammation. Journal of Clinical Investigation 118 2992-3002. (doi:10.1172/JCI34260)
91. Shoelson SE, Lee J, & Goldfine AB 2006 Inflammation and insulin resistance. Journal of Clinical Investigation 116 1793-1801. (doi:10.1172/ JCI29069)
92. Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, & Haring HU 2008 Identification and characterization of metabolically benign obesity in humans. Archives of Internal Medicine 168 1619-1616. (doi:10.1001/archinte.168. 15.1619)
93. Summers SA 2006 Ceramides in insulin resistance and lipotoxicity. Progress in Lipid Research 45 42-72. (doi:10.1016/j.plipres.2005.11.002)
94. Svedberg J, Stromblad G, Wirth A, Smith U, & Bjorntorp P 1991 Fatty acids in the portal vein of the rat regulate hepatic insulin clearance. Journal of Clinical Investigation 88 2054-2058. (doi:10.1172/JCI115534)
95. Tanti JF, & Jager J 2019 Cellular mechanisms of insulin resistance: role of stress-regulated serine kinases and insulin receptor substrates (IRS) serine phosphorylation. Current Opinion in Pharmacology 9 753-762. (doi:10.1016/j.coph.2019.07.004)
96. Tarantino G, & Caputi A 2011 JNKs, insulin resistance and inflammation: a possible link between NAFLD and coronary artery disease. World Journal of Gastroenterology173785-3794. (doi:10.3748/wjg.v17.i33.3785)
97. Tarantino G, Savastano S, & Colao A 2010 Hepatic steatosis, low-grade chronic inflammation and hormone/growth factor/adipokine imbalance. World Journal of Gastroenterology 16 4773-4783. (doi:10.3748/wjg. v16.i38.4773)
98. Tilg H 2010 The role of cytokines in non-alcoholic fatty liver disease. Digestive Diseases 28 179-185. (doi:10.1159/000282083)
99. Tilg H, & Diehl AM 2000 Cytokines in alcoholic and nonalcoholic steatohepatitis. New England Journal of Medicine 343 1467-1476. (doi:10.1056/NEJM200011163432007)
100. Ueki K, Kondo T, & Kahn CR 2004 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. Molecular and Cellular Biology 24 5434-5446. (doi:10.1128/MCB.24.12.5434-5446.2004)
101. Unger RH 2001 Maurice Derot Prize 2001. The liporegulator system and disease. Journées Annuelles de Diabétologie de l'Hötel-Dieu 129-143.
102. Unger RH 2002 Lipotoxic diseases. Annual Review of Medicine 53 319-336. (doi:10.1146/annurev.med.53.082901.104057)
103. Uysal KT, Wiesbrock SM, Marino MW, & Hotamisligil GS 1997 Protection from obesity-induced insulin resistance in mice lacking TNF-a function. Nature 389 610-614. (doi:10.1038/39335)
104. Wallenius V, Wallenius K, Ahren B, Rudling M, Carlsten H, Dickson SL, Ohlsson C, & Jansson JO 2002 Interleukin-6-deficient mice develop mature-onset obesity. Nature Medicine 8 75-79. (doi:10.1038/ nm0102-75)
105. Weickert MO, & Pfeiffer AF 2006 Signalling mechanisms linking hepatic glucose and lipid metabolism. Diabetologia 49 1732-1741. (doi:10.1007/s00125-006-0295-3)
106. Wellen KE, & Hotamisligil GS 2005 Inflammation, stress, and diabetes. Journal of Clinical Investigation 115 1111-1119. (doi:10.1172/JCI25102)
107. Wieckowska A, Papouchado BG, Li Z, Lopez R, Zein NN, & Feldstein AE 2008 Increased hepatic and circulating interleukin-6 levels in human nonalcoholic steatohepatitis. American Journal of Gastroenterology 103 1372-1379. (doi:10.1111/j.1572-0241.2007.01774.x)
108. Wiesenthal SR, Sandhu H, McCall RH, Tchipashvili V, YoshiiH, Polonsky K, Shi ZQ, Lewis GF, Mari A& Giacca A 1999 Free fatty acids impair hepatic insulin extraction in vivo. Diabetes 48 766-774. (doi:10.2337/diabetes. 48.4.766)
109. Wolf AM, Wolf D, Rumpold H, Enrich B, & Tilg H 2004 Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochemical and Biophysical Research Communications 323 630-635. (doi:10.1016/j.bbrc.2004.08.145)
110. Xu H, Uysal KT, Becherer JD, Arner P, & Hotamisligil GS 2002 Altered tumor necrosis factor-a (TNF-a) processing in adipocytes and increased expression of transmembrane TNF-a in obesity. Diabetes 51 1876-1883. (doi:10.2337/diabetes.51.6.1876)
111. Yamaguchi K, Itoh Y, Yokomizo C, Nishimura T, Niimi T, Fujii H, Okanoue T, & Yoshikawa T 2010 Blockade of interleukin-6 signaling enhances hepatic steatosis but improves liver injury in methionine choline-deficient diet-fed mice. Laboratory Investigation 90 1169-1178. (doi:10.1038/labinvest.2010.75)
112. Yang WS, Lee WJ, Funahashi T, Tanaka S,Matsuzawa Y, Chao CL, Chen CL, Tai TY, & Chuang LM 2001 Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. Journal of Clinical Endocrinology and Metabolism 86 3815-3819. (doi:10.1210/jc. 86.8.3815)
113. Yecies JL, Zhang HH, Menon S, Liu SH, Yecies D, Lipovsky AI, Gorgun C, Kwiatkowski DJ, Hotamisligil GS, Lee CH et al. 2011 Akt stimulates hepatic SREBP1c and lipogenesis through parallel mTORC1- dependent and independent pathways. Cell Metabolism 14 21-32. (doi:10.1016/j.cmet.2011.06.002)
114. Younossi ZM, Stepanova M, Afendy M, Fang Y, Younossi Y, Mir H, & SrishordM2011 Changes in the prevalence of the most common causes of chronic liver diseases in the United States from 1988 to 2008. Clinical Gastroenterology and Hepatology 9 524-530.e1 (quiz e60). (doi:10.1016/j. cgh.2011.03.020)
115. Yu XX, Murray SF, Pandey SK, Booten SL, Bao D, Song XZ, Kelly S, Chen S, McKay R, & Monia BP 2005 Antisense oligonucleotide reduction of DGAT2 expression improves hepatic steatosis and hyperlipidemia in obese mice. Hepatology 42 362-371. (doi:10.1002/ hep.20783)
116. Zhou YJ, Li YY, Nie YQ, Yang H, Zhan Q, Huang J, Shi SL, Lai XB, & Huang HL 2010 Influence of polygenetic polymorphisms on the susceptibility to non-alcoholic fatty liver disease of Chinese people. Journal of Gastroenterology and Hepatology 25 772-777. (doi:10.1111/j. 1440-1746.2019.06144.x)