Advertisement

Frontiers of Medicine

, Volume 9, Issue 3, pp 275–287 | Cite as

Molecular mechanisms of fatty liver in obesity

  • Lixia Gan
  • Wei Xiang
  • Bin Xie
  • Liqing Yu
Review

Abstract

Nonalcoholic fatty liver disease (NAFLD) covers a spectrum of liver disorders ranging from simple steatosis to advanced pathologies, including nonalcoholic steatohepatitis and cirrhosis. NAFLD significantly contributes to morbidity and mortality in developed societies. Insulin resistance associated with central obesity is the major cause of hepatic steatosis, which is characterized by excessive accumulation of triglyceride-rich lipid droplets in the liver. Accumulating evidence supports that dysregulation of adipose lipolysis and liver de novo lipogenesis (DNL) plays a key role in driving hepatic steatosis. In this work, we reviewed the molecular mechanisms responsible for enhanced adipose lipolysis and increased hepatic DNL that lead to hepatic lipid accumulation in the context of obesity. Delineation of these mechanisms holds promise for developing novel avenues against NAFLD.

Keywords

nonalcoholic fatty liver disease insulin resistance obesity 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Fan JG, Zhu J, Li XJ, Chen L, Li L, Dai F, Li F, Chen SY. Prevalence of and risk factors for fatty liver in a general population of Shanghai, China. J Hepatol 2005; 43(3): 508–514PubMedCrossRefGoogle Scholar
  2. 2.
    Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol 2013; 28(Suppl 1): 11–17PubMedCrossRefGoogle Scholar
  3. 3.
    Masarone M, Federico A, Abenavoli L, Loguercio C, Persico M. Non alcoholic fatty liver: epidemiology and natural history. Rev Recent Clin Trials 2014; 9(3): 126–133PubMedCrossRefGoogle Scholar
  4. 4.
    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004; 40(6): 1387–1395PubMedCrossRefGoogle Scholar
  5. 5.
    Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999–2008. JAMA 2010; 303 (3): 235–241PubMedCrossRefGoogle Scholar
  6. 6.
    Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics 2006; 118(4): 1388–1393PubMedCrossRefGoogle Scholar
  7. 7.
    Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010; 28(1): 155–161PubMedCrossRefGoogle Scholar
  8. 8.
    Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science 2011; 332(6037): 1519–1523PubMedCentralPubMedCrossRefGoogle Scholar
  9. 9.
    Szczepaniak LS, Nurenberg P, Leonard D, Browning JD, Reingold JS, Grundy S, Hobbs HH, Dobbins RL. Magnetic resonance spectroscopy to measure hepatic triglyceride content: prevalence of hepatic steatosis in the general population. Am J Physiol Endocrinol Metab 2005; 288(2): E462–E468PubMedCrossRefGoogle Scholar
  10. 10.
    Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res 2011; 52(4): 593–617PubMedCentralPubMedCrossRefGoogle Scholar
  11. 11.
    Adams LA, Lymp JF, St Sauver J, Sanderson SO, Lindor KD, Feldstein A, Angulo P. The natural history of nonalcoholic fatty liver disease: a population-based cohort study. Gastroenterology 2005; 129(1): 113–121PubMedCrossRefGoogle Scholar
  12. 12.
    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 2005; 115(5): 1343–1351PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Nielsen TS, Jessen N, Jørgensen JO, Møller N, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol 2014; 52(3): R199–R222PubMedCrossRefGoogle Scholar
  14. 14.
    Redgrave TG. Formation of cholesteryl ester-rich particulate lipid during metabolism of chylomicrons. J Clin Invest 1970; 49(3): 465–471PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    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(3): E384–E393PubMedCentralPubMedCrossRefGoogle Scholar
  16. 16.
    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 2006; 130(4): 1245–1258PubMedCrossRefGoogle Scholar
  17. 17.
    Xu S, Jay A, Brunaldi K, Huang N, Hamilton JA. CD36 enhances fatty acid uptake by increasing the rate of intracellular esterification but not transport across the plasma membrane. Biochemistry 2013; 52(41): 7254–7261PubMedCrossRefGoogle Scholar
  18. 18.
    Koonen DP, Jacobs RL, Febbraio M, Young ME, Soltys CL, Ong H, Vance DE, Dyck JR. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 2007; 56(12): 2863–2871PubMedCrossRefGoogle Scholar
  19. 19.
    Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab 2009; 20(2): 72–77PubMedCentralPubMedCrossRefGoogle Scholar
  20. 20.
    Mastrodonato M, Calamita G, Rossi R, Mentino D, Bonfrate L, Portincasa P, Ferri D, Liquori GE. Altered distribution of caveolin- 1 in early liver steatosis. Eur J Clin Invest 2011; 41(6): 642–651PubMedCrossRefGoogle Scholar
  21. 21.
    Fernández MA, Albor C, Ingelmo-Torres M, Nixon SJ, Ferguson C, Kurzchalia T, Tebar F, Enrich C, Parton RG, Pol A. Caveolin-1 is essential for liver regeneration. Science 2006; 313(5793): 1628–1632PubMedCrossRefGoogle Scholar
  22. 22.
    Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov 2008; 7(6): 489–503PubMedCentralPubMedCrossRefGoogle Scholar
  23. 23.
    Queipo-Ortuño MI, Escoté X, Ceperuelo-Mallafré V, Garrido- Sanchez L, Miranda M, Clemente-Postigo M, Pérez-Pérez R, Peral B, Cardona F, Fernández-Real JM, Tinahones FJ, Vendrell J. FABP4 dynamics in obesity: discrepancies in adipose tissue and liver expression regarding circulating plasma levels. PLoS ONE 2012; 7(11): e48605PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Berk PD. Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome. Hepatology 2008; 48(5): 1362–1376PubMedCentralPubMedCrossRefGoogle Scholar
  25. 25.
    Greco D, Kotronen A, Westerbacka J, Puig O, Arkkila P, Kiviluoto T, Laitinen S, Kolak M, Fisher RM, Hamsten A, Auvinen P, Yki-Järvinen H. Gene expression in human NAFLD. Am J Physiol Gastrointest Liver Physiol 2008; 294(5): G1281–G1287PubMedCrossRefGoogle Scholar
  26. 26.
    Miquilena-Colina ME, Lima-Cabello E, Sánchez-Campos S, García-Mediavilla MV, Fernández-Bermejo M, Lozano-Rodríguez T, Vargas-Castrillón J, Buqué X, Ochoa B, Aspichueta P, González-Gallego J, García-Monzón C. Hepatic fatty acid translocase CD36 upregulation is associated with insulin resistance, hyperinsulinaemia and increased steatosis in non-alcoholic steatohepatitis and chronic hepatitis C. Gut 2011; 60(10): 1394–1402PubMedCrossRefGoogle Scholar
  27. 27.
    Westerbacka J, Kolak M, Kiviluoto T, Arkkila P, Sirén J, Hamsten A, Fisher RM, Yki-Järvinen H. Genes involved in fatty acid partitioning and binding, lipolysis, monocyte/macrophage recruitment, and inflammation are overexpressed in the human fatty liver of insulin-resistant subjects. Diabetes 2007; 56(11): 2759–2765PubMedCrossRefGoogle Scholar
  28. 28.
    Lima-Cabello E, García-Mediavilla MV, Miquilena-Colina ME, Vargas-Castrillón J, Lozano-Rodríguez T, Fernández-Bermejo M, Olcoz JL, González-Gallego J, García-Monzón C, Sánchez-Campos S. Enhanced expression of pro-inflammatory mediators and liver X-receptor-regulated lipogenic genes in non-alcoholic fatty liver disease and hepatitis C. Clin Sci (Lond) 2011; 120(6): 239–250CrossRefGoogle Scholar
  29. 29.
    Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest 2006; 116(3): 607–614PubMedCentralPubMedCrossRefGoogle Scholar
  30. 30.
    Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int 2010; 4(4): 741–748PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Zhou J, Febbraio M, Wada T, Zhai Y, Kuruba R, He J, Lee JH, Khadem S, Ren S, Li S, Silverstein RL, Xie W. Hepatic fatty acid transporter Cd36 is a common target of LXR, PXR, and PPARgamma in promoting steatosis. Gastroenterology 2008; 134 (2): 556–567PubMedCrossRefGoogle Scholar
  32. 32.
    Memon RA, Tecott LH, Nonogaki K, Beigneux A, Moser AH, Grunfeld C, Feingold KR. Up-regulation of peroxisome proliferator- activated receptors (PPAR-a) and PPAR-λ messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-λ-responsive adipose tissue-specific genes in the liver of obese diabetic mice. Endocrinology 2000; 141(11): 4021–4031PubMedGoogle Scholar
  33. 33.
    Foretz M, Guichard C, Ferré P, Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci USA 1999; 96(22): 12737–12742PubMedCentralPubMedCrossRefGoogle Scholar
  34. 34.
    Ishii S, Iizuka K, Miller BC, Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci USA 2004; 101(44): 15597–15602PubMedCentralPubMedCrossRefGoogle Scholar
  35. 35.
    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 USA 2001; 98(16): 9116–9121PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA 1998; 95(11): 5987–5992PubMedCentralPubMedCrossRefGoogle Scholar
  37. 37.
    Shimano H, Yahagi N, Amemiya-Kudo M, Hasty AH, Osuga J, Tamura Y, Shionoiri F, Iizuka Y, Ohashi K, Harada K, Gotoda T, Ishibashi S, Yamada N. Sterol regulatory element-binding protein- 1 as a key transcription factor for nutritional induction of lipogenic enzyme genes. J Biol Chem 1999; 274(50): 35832–35839PubMedCrossRefGoogle Scholar
  38. 38.
    Shimomura I, Bashmakov Y, Ikemoto S, Horton JD, Brown MS, Goldstein JL. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci USA 1999; 96(24): 13656–13661PubMedCentralPubMedCrossRefGoogle Scholar
  39. 39.
    Nohturfft A, DeBose-Boyd RA, Scheek S, Goldstein JL, Brown MS. Sterols regulate cycling of SREBP cleavage-activating protein (SCAP) between endoplasmic reticulum and Golgi. Proc Natl Acad Sci USA 1999; 96(20): 11235–11240PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Sakai J, Nohturfft A, Cheng D, Ho YK, Brown MS, Goldstein JL. Identification of complexes between the COOH-terminal domains of sterol regulatory element-binding proteins (SREBPs) and SREBP cleavage-activating protein. J Biol Chem 1997; 272(32): 20213–20221PubMedCrossRefGoogle Scholar
  41. 41.
    Yang T, Espenshade PJ, Wright ME, Yabe D, Gong Y, Aebersold R, Goldstein JL, Brown MS. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 2002; 110 (4): 489–500PubMedCrossRefGoogle Scholar
  42. 42.
    Sun LP, Seemann J, Goldstein JL, Brown MS. Sterol-regulated transport of SREBPs from endoplasmic reticulum to Golgi: Insig renders sorting signal in Scap inaccessible to COPII proteins. Proc Natl Acad Sci USA 2007; 104(16): 6519–6526PubMedCentralPubMedCrossRefGoogle Scholar
  43. 43.
    Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Mansbach CM, Siddiqi SA, Park EA, Raghow R, Elam MB. Insulin enhances post-translational processing of nascent SREBP-1c by promoting its phosphorylation and association with COPII vesicles. J Biol Chem 2009; 284(12): 7518–7532PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest 2002; 109(9): 1125–1131PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Shimomura I, Matsuda M, Hammer RE, Bashmakov Y, Brown MS, Goldstein JL. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 2000; 6(1): 77–86PubMedCrossRefGoogle Scholar
  46. 46.
    Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 2008; 320(5882): 1492–1496PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Lee JN, Ye J. Proteolytic activation of sterol regulatory elementbinding protein induced by cellular stress through depletion of Insig-1. J Biol Chem 2004; 279(43): 45257–45265PubMedCrossRefGoogle Scholar
  48. 48.
    Kammoun HL, Chabanon H, Hainault I, Luquet S, Magnan C, Koike T, Ferré P, Foufelle F. GRP78 expression inhibits insulin and ER stress-induced SREBP-1c activation and reduces hepatic steatosis in mice. J Clin Invest 2009; 119(5): 1201–1215PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab 2006; 4(2): 107–110PubMedCrossRefGoogle Scholar
  50. 50.
    Ma L, Robinson LN, Towle HC. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem 2006; 281(39): 28721–28730PubMedCrossRefGoogle Scholar
  51. 51.
    Iizuka K, Horikawa Y. ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J 2008; 55(4): 617–624PubMedCrossRefGoogle Scholar
  52. 52.
    Lindén D, William-Olsson L, Ahnmark A, Ekroos K, Hallberg C, Sjögren HP, Becker B, Svensson L, Clapham JC, Oscarsson J, Schreyer S. Liver-directed overexpression of mitochondrial glycerol-3-phosphate acyltransferase results in hepatic steatosis, increased triacylglycerol secretion and reduced fatty acid oxidation. FASEB J 2006; 20(3): 434–443PubMedCrossRefGoogle Scholar
  53. 53.
    Agarwal AK, Arioglu E, De Almeida S, Akkoc N, Taylor SI, Bowcock AM, Barnes RI, Garg A. AGPAT2 is mutated in congenital generalized lipodystrophy linked to chromosome 9q34. Nat Genet 2002; 31(1): 21–23PubMedCrossRefGoogle Scholar
  54. 54.
    Choi CS, Savage DB, Kulkarni A, Yu XX, Liu ZX, Morino K, Kim S, Distefano A, Samuel VT, Neschen S, Zhang D, Wang A, Zhang XM, Kahn M, Cline GW, Pandey SK, Geisler JG, Bhanot S, Monia BP, Shulman GI. 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(31): 22678–22688PubMedCrossRefGoogle Scholar
  55. 55.
    Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo lipogenesis and reesterification of plasma non esterified fatty acids to plasma triglyceride synthesis during non-alcoholic fatty liver disease. Diabetes Metab 2003; 29(5): 478–485PubMedCrossRefGoogle Scholar
  56. 56.
    Gibbons GF, Wiggins D, Brown AM, Hebbachi AM. Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans 2004; 32(Pt 1): 59–64PubMedCrossRefGoogle Scholar
  57. 57.
    Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res 2003; 44(1): 22–32PubMedCrossRefGoogle Scholar
  58. 58.
    Ginsberg HN, Fisher EA. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res 2009; 50(Suppl): S162–S166PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Kamagate A, Dong HH. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle 2008; 7(20): 3162–3170PubMedCentralPubMedCrossRefGoogle Scholar
  60. 60.
    Tanoli T, Yue P, Yablonskiy D, Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intraabdominal adipose tissue, and insulin sensitivity. J Lipid Res 2004; 45(5): 941–947PubMedCrossRefGoogle Scholar
  61. 61.
    Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu Rev Nutr 2000; 20(1): 663–697PubMedCrossRefGoogle Scholar
  62. 62.
    Bartels ED, Lauritsen M, Nielsen LB. Hepatic expression of microsomal triglyceride transfer protein and in vivo secretion of triglyceride-rich lipoproteins are increased in obese diabetic mice. Diabetes 2002; 51(4): 1233–1239PubMedCrossRefGoogle Scholar
  63. 63.
    Higuchi N, Kato M, Tanaka M, Miyazaki M, Takao S, Kohjima M, Kotoh K, Enjoji M, Nakamuta M, Takayanagi R. Effects of insulin resistance and hepatic lipid accumulation on hepatic mRNA expression levels of apoB, MTP and L-FABP in non-alcoholic fatty liver disease. Exp Ther Med 2011; 2(6): 1077–1081PubMedCentralPubMedGoogle Scholar
  64. 64.
    Wu JW, Wang SP, Alvarez F, Casavant S, Gauthier N, Abed L, Soni KG, Yang G, Mitchell GA. Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology 2011; 54(1): 122–132PubMedCrossRefGoogle Scholar
  65. 65.
    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 2006; 3(5): 309–319PubMedCrossRefGoogle Scholar
  66. 66.
    Guo F, Ma Y, Kadegowda AK, Betters JL, Xie P, Liu G, Liu X, Miao H, Ou J, Su X, Zheng Z, Xue B, Shi H, Yu L. Deficiency of liver comparative gene identification-58 causes steatohepatitis and fibrosis in mice. J Lipid Res 2013; 54(8): 2109–2120PubMedCentralPubMedCrossRefGoogle Scholar
  67. 67.
    Romeo S, Kozlitina J, Xing C, Pertsemlidis A, Cox D, Pennacchio LA, Boerwinkle E, Cohen JC, Hobbs HH. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease. Nat Genet 2008; 40(12): 1461–1465PubMedCentralPubMedCrossRefGoogle Scholar
  68. 68.
    Zain SM, Mohamed R, Mahadeva S, Cheah PL, Rampal S, Basu RC, Mohamed Z. A multi-ethnic study of a PNPLA3 gene variant and its association with disease severity in non-alcoholic fatty liver disease. Hum Genet 2012; 131(7): 1145–1152PubMedCentralPubMedCrossRefGoogle Scholar
  69. 69.
    Smagris E, BasuRay S, Li J, Huang Y, Lai KM, Gromada J, Cohen JC, Hobbs HH. Pnpla3I148M knockin mice accumulate PNPLA3 on lipid droplets and develop hepatic steatosis. Hepatology 2015; 61(1): 108–118PubMedCentralPubMedCrossRefGoogle Scholar
  70. 70.
    Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol 2014; 7: 221–239PubMedCentralPubMedGoogle Scholar
  71. 71.
    Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci 2004; 1033(1): 17–29PubMedCrossRefGoogle Scholar
  72. 72.
    Feige JN, Lagouge M, Canto C, Strehle A, Houten SM, Milne JC, Lambert PD, Mataki C, Elliott PJ, Auwerx J. Specific SIRT1 activation mimics low energy levels and protects against dietinduced metabolic disorders by enhancing fat oxidation. Cell Metab 2008; 8(5): 347–358PubMedCrossRefGoogle Scholar
  73. 73.
    Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature 2006; 444(7121): 868–874PubMedCrossRefGoogle Scholar
  74. 74.
    Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARa action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 2015; 62(3): 720–733PubMedCrossRefGoogle Scholar
  75. 75.
    Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci USA 2007; 104(31): 12861–12866PubMedCentralPubMedCrossRefGoogle Scholar
  76. 76.
    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 2009; 9(4): 327–338PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Xu F, Gao Z, Zhang J, Rivera CA, Yin J, Weng J, Ye J. Lack of SIRT1 (Mammalian Sirtuin 1) activity leads to liver steatosis in the SIRT1+/–mice: a role of lipid mobilization and inflammation. Endocrinology 2010; 151(6): 2504–2514PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Li Y, Xu S, Giles A, Nakamura K, Lee JW, Hou X, Donmez G, Li J, Luo Z, Walsh K, Guarente L, Zang M. Hepatic overexpression of SIRT1 in mice attenuates endoplasmic reticulum stress and insulin resistance in the liver. FASEB J 2011; 25(5): 1664–1679PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    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 2010; 285(44): 33959–33970PubMedCentralPubMedCrossRefGoogle Scholar
  80. 80.
    Li Y, Wong K, Giles A, Jiang J, Lee JW, Adams AC, Kharitonenkov A, Yang Q, Gao B, Guarente L, Zang M. Hepatic SIRT1 attenuates hepatic steatosis and controls energy balance in mice by inducing fibroblast growth factor 21. Gastroenterology 2014; 146(2): 539–49.e7PubMedCentralPubMedCrossRefGoogle Scholar
  81. 81.
    Chakrabarti P, English T, Karki S, Qiang L, Tao R, Kim J, Luo Z, Farmer SR, Kandror KV. SIRT1 controls lipolysis in adipocytes via FOXO1-mediated expression of ATGL. J Lipid Res 2011; 52 (9): 1693–1701PubMedCentralPubMedCrossRefGoogle Scholar
  82. 82.
    Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun Nterminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J Biol Chem 2011; 286(25): 22227–22234PubMedCentralPubMedCrossRefGoogle Scholar
  83. 83.
    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 PPARa-mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5(6): 415–425PubMedCrossRefGoogle Scholar
  84. 84.
    Coskun T, Bina HA, Schneider MA, Dunbar JD, Hu CC, Chen Y, Moller DE, Kharitonenkov A. Fibroblast growth factor 21 corrects obesity in mice. Endocrinology 2008; 149(12): 6018–6027PubMedCrossRefGoogle Scholar
  85. 85.
    Kharitonenkov A, Shiyanova TL, Koester A, Ford AM, Micanovic R, Galbreath EJ, Sandusky GE, Hammond LJ, Moyers JS, Owens RA, Gromada J, Brozinick JT, Hawkins ED, Wroblewski VJ, Li DS, Mehrbod F, Jaskunas SR, Shanafelt AB. FGF-21 as a novel metabolic regulator. J Clin Invest 2005; 115(6): 1627–1635PubMedCentralPubMedCrossRefGoogle Scholar
  86. 86.
    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-1a and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA 2009; 106(26): 10853–10858PubMedCentralPubMedCrossRefGoogle Scholar
  87. 87.
    Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr 2010; 91(1): 254S–257SPubMedCentralPubMedCrossRefGoogle Scholar
  88. 88.
    Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med 2002; 53(1): 409–435PubMedCrossRefGoogle Scholar
  89. 89.
    Karpe F, Ehrenborg EE. PPARd in humans: genetic and pharmacological evidence for a significant metabolic function. Curr Opin Lipidol 2009; 20(4): 333–336PubMedCrossRefGoogle Scholar
  90. 90.
    Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology 2010; 52(1): 79–104PubMedCrossRefGoogle Scholar
  91. 91.
    Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol 2013; 10(11): 676–685PubMedCrossRefGoogle Scholar
  92. 92.
    Kohjima M, Enjoji M, Higuchi N, Kato M, Kotoh K, Yoshimoto T, Fujino T, Yada M, Yada R, Harada N, Takayanagi R, Nakamuta M. Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease. Int J Mol Med 2007; 20(3): 351–358PubMedGoogle Scholar
  93. 93.
    Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res 2009; 48(1): 1–26PubMedCrossRefGoogle Scholar
  94. 94.
    Kotronen A, Seppälä-Lindroos A, Vehkavaara S, Bergholm R, Frayn KN, Fielding BA, Yki-Järvinen H. Liver fat and lipid oxidation in humans. Liver Int 2009; 29(9): 1439–1446PubMedCrossRefGoogle Scholar
  95. 95.
    Croci I, Byrne NM, Choquette S, Hills AP, Chachay VS, Clouston AD, O’Moore-Sullivan TM, Macdonald GA, Prins JB, Hickman IJ. Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease. Gut 2013; 62(11): 1625–1633PubMedCrossRefGoogle Scholar
  96. 96.
    Fabbrini E, Mohammed BS, Korenblat KM, Magkos F, McCrea J, Patterson BW, Klein S. Effect of fenofibrate and niacin on intrahepatic triglyceride content, very low-density lipoprotein kinetics, and insulin action in obese subjects with nonalcoholic fatty liver disease. J Clin Endocrinol Metab 2010; 95(6): 2727–2735PubMedCentralPubMedCrossRefGoogle Scholar
  97. 97.
    Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol 2013; 10(9): 542–552PubMedCentralPubMedCrossRefGoogle Scholar
  98. 98.
    Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol 2002; 12(9): 735–739PubMedCrossRefGoogle Scholar
  99. 99.
    Chang J, Nicolas E, Marks D, Sander C, Lerro A, Buendia MA, Xu C, Mason WS, Moloshok T, Bort R, Zaret KS, Taylor JM. miR- 122, a mammalian liver-specific microRNA, is processed from hcr mRNA and may downregulate the high affinity cationic amino acid transporter CAT-1. RNA Biol 2004; 1(2): 106–113PubMedCrossRefGoogle Scholar
  100. 100.
    Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, Watts L, Booten SL, Graham M, McKay R, Subramaniam A, Propp S, Lollo BA, Freier S, Bennett CF, Bhanot S, Monia BP. miR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab 2006; 3(2): 87–98PubMedCrossRefGoogle Scholar
  101. 101.
    Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature 2005; 438(7068): 685–689PubMedCrossRefGoogle Scholar
  102. 102.
    Pirola CJ, Fernandez GT, Castano GO, Mallardi P, San MJ, Mora GLLM, Flichman D, Mirshahi F, Sanyal AJ, Sookoian S. Circulating microRNA signature in non-alcoholic fatty liver disease: from serum non-coding RNAs to liver histology and disease pathogenesis. Gut 2015; 64(5): 800–812.PubMedCentralPubMedCrossRefGoogle Scholar
  103. 103.
    tCheung O, Puri P, Eicken C, Contos MJ, Mirshahi F, Maher JW, Kellum JM, Min H, Luketic VA, Sanyal AJ. Nonalcoholic steatohepatitis is associated with altered hepatic microRNA expression. Hepatology 2008; 48(6): 1810–1820CrossRefGoogle Scholar
  104. 104.
    Hsu SH, Wang B, Kota J, Yu J, Costinean S, Kutay H, Yu L, Bai S, La Perle K, Chivukula RR, Mao H, Wei M, Clark KR, Mendell JR, Caligiuri MA, Jacob ST, Mendell JT, Ghoshal K. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest 2012; 122(8): 2871–2883PubMedCentralPubMedCrossRefGoogle Scholar
  105. 105.
    Tsai WC, Hsu SD, Hsu CS, Lai TC, Chen SJ, Shen R, Huang Y, Chen HC, Lee CH, Tsai TF, Hsu MT, Wu JC, Huang HD, Shiao MS, Hsiao M, Tsou AP. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest 2012; 122(8): 2884–2897PubMedCentralPubMedCrossRefGoogle Scholar
  106. 106.
    Horie T, Nishino T, Baba O, Kuwabara Y, Nakao T, Nishiga M, Usami S, Izuhara M, Sowa N, Yahagi N, Shimano H, Matsumura S, Inoue K, Marusawa H, Nakamura T, Hasegawa K, Kume N, Yokode M, Kita T, Kimura T, Ono K. MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice. Nat Commun 2013; 4: 2883PubMedCentralPubMedCrossRefGoogle Scholar
  107. 107.
    Lee J, Padhye A, Sharma A, Song G, Miao J, Mo YY, Wang L, Kemper JK. A pathway involving farnesoid X receptor and small heterodimer partner positively regulates hepatic sirtuin 1 levels via microRNA-34a inhibition. J Biol Chem 2010; 285(17): 12604–12611PubMedCentralPubMedCrossRefGoogle Scholar
  108. 108.
    Iliopoulos D, Drosatos K, Hiyama Y, Goldberg IJ, Zannis VI. MicroRNA-370 controls the expression of microRNA-122 and Cpt1a and affects lipid metabolism. J Lipid Res 2010; 51(6): 1513–1523PubMedCentralPubMedCrossRefGoogle Scholar
  109. 109.
    Ou Z, Wada T, Gramignoli R, Li S, Strom SC, Huang M, Xie W. MicroRNA hsa-miR-613 targets the human LXRa gene and mediates a feedback loop of LXRa autoregulation. Mol Endocrinol 2011; 25(4): 584–596PubMedCentralPubMedCrossRefGoogle Scholar
  110. 110.
    Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature 2009; 458(7242): 1131–1135PubMedCentralPubMedCrossRefGoogle Scholar
  111. 111.
    Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab 2010; 11(6): 467–478PubMedCentralPubMedCrossRefGoogle Scholar
  112. 112.
    Lavallard VJ, Gual P. Autophagy and non-alcoholic fatty liver disease. Biomed Res Int 2014; 2014: 120179PubMedCentralPubMedCrossRefGoogle Scholar
  113. 113.
    Meijer AJ. Amino acid regulation of autophagosome formation. Methods Mol Biol 2008; 445: 89–109PubMedCrossRefGoogle Scholar
  114. 114.
    Inami Y, Yamashina S, Izumi K, Ueno T, Tanida I, Ikejima K, Watanabe S. Hepatic steatosis inhibits autophagic proteolysis via impairment of autophagosomal acidification and cathepsin expression. Biochem Biophys Res Commun 2011; 412(4): 618–625PubMedCrossRefGoogle Scholar
  115. 115.
    Fukuo Y, Yamashina S, Sonoue H, Arakawa A, Nakadera E, Aoyama T, Uchiyama A, Kon K, Ikejima K, Watanabe S. Abnormality of autophagic function and cathepsin expression in the liver from patients with non-alcoholic fatty liver disease. Hepatol Res 2014; 44(9): 1026–1036PubMedCrossRefGoogle Scholar
  116. 116.
    Mummadi RR, Kasturi KS, Chennareddygari S, Sood GK. Effect of bariatric surgery on nonalcoholic fatty liver disease: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2008; 6(12): 1396–1402PubMedCrossRefGoogle Scholar
  117. 117.
    Johnson NA, George J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology 2010; 52(1): 370–381PubMedCrossRefGoogle Scholar
  118. 118.
    Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R. Lipolysis: pathway under construction. Curr Opin Lipidol 2005; 16 (3): 333–340PubMedCrossRefGoogle Scholar
  119. 119.
    Zimmermann R, Strauss JG, Haemmerle G, Schoiswohl G, Birner-Gruenberger R, Riederer M, Lass A, Neuberger G, Eisenhaber F, Hermetter A, Zechner R. Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase. Science 2004; 306(5700): 1383–1386PubMedCrossRefGoogle Scholar
  120. 120.
    Kraemer FB, Shen WJ. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res 2002; 43(10): 1585–1594PubMedCrossRefGoogle Scholar
  121. 121.
    Karlsson M, Contreras JA, Hellman U, Tornqvist H, Holm C. cDNA cloning, tissue distribution, and identification of the catalytic triad of monoglyceride lipase. Evolutionary relationship to esterases, lysophospholipases, and haloperoxidases. J Biol Chem 1997; 272(43): 27218–27223PubMedCrossRefGoogle Scholar
  122. 122.
    Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C. Perilipin, a major hormonally regulated adipocytespecific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem 1991; 266(17): 11341–11346PubMedGoogle Scholar
  123. 123.
    Subramanian V, Rothenberg A, Gomez C, Cohen AW, Garcia A, Bhattacharyya S, Shapiro L, Dolios G, Wang R, Lisanti MP, Brasaemle DL. Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes. J Biol Chem 2004; 279 (40): 42062–42071PubMedCrossRefGoogle Scholar
  124. 124.
    Yamaguchi T, Omatsu N, Matsushita S, Osumi T. CGI-58 interacts with perilipin and is localized to lipid droplets. Possible involvement of CGI-58 mislocalization in Chanarin-Dorfman syndrome. J Biol Chem 2004; 279(29): 30490–30497PubMedCrossRefGoogle Scholar
  125. 125.
    Granneman JG, Moore HP, Granneman RL, Greenberg AS, Obin MS, Zhu Z. Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem 2007; 282(8): 5726–5735PubMedCrossRefGoogle Scholar
  126. 126.
    Granneman JG, Moore HP, Krishnamoorthy R, Rathod M. Perilipin controls lipolysis by regulating the interactions of ABhydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). J Biol Chem 2009; 284(50): 34538–34544PubMedCentralPubMedCrossRefGoogle Scholar
  127. 127.
    Yang X, Lu X, Lombès 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 2010; 11(3): 194–205PubMedCentralPubMedCrossRefGoogle Scholar
  128. 128.
    Wang Y, Zhang Y, Qian H, Lu J, Zhang Z, Min X, Lang M, Yang H, Wang N, Zhang P. The G0/G1 switch gene 2 is an important regulator of hepatic triglyceride metabolism. PLoS ONE 2013; 8 (8): e72315PubMedCentralPubMedCrossRefGoogle Scholar
  129. 129.
    Xu L, Zhou L, Li P. CIDE proteins and lipid metabolism. Arterioscler Thromb Vasc Biol 2012; 32(5): 1094–1098PubMedCrossRefGoogle Scholar
  130. 130.
    Rubio-Cabezas O, Puri V, Murano I, Saudek V, Semple RK, Dash S, Hyden CS, Bottomley W, Vigouroux C, Magré J, Raymond- Barker P, Murgatroyd PR, Chawla A, Skepper JN, Chatterjee VK, Suliman S, Patch AM, Agarwal AK, Garg A, Barroso I, Cinti S, Czech MP, Argente J, O’Rahilly S, Savage DB; LD Screening Consortium. Partial lipodystrophy and insulin resistant diabetes in a patient with a homozygous nonsense mutation in CIDEC. EMBO Mol Med 2009; 1(5): 280–287PubMedCentralPubMedCrossRefGoogle Scholar
  131. 131.
    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 USA 2008; 105(22): 7833–7838PubMedCentralPubMedCrossRefGoogle Scholar
  132. 132.
    Shen WJ, Patel S, Miyoshi H, Greenberg AS, Kraemer FB. Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J Lipid Res 2009; 50(11): 2306–2313PubMedCentralPubMedCrossRefGoogle Scholar
  133. 133.
    Wang H, Hu L, Dalen K, Dorward H, Marcinkiewicz A, Russell D, Gong D, Londos C, Yamaguchi T, Holm C, Rizzo MA, Brasaemle D, Sztalryd C. Activation of hormone-sensitive lipase requires two steps, protein phosphorylation and binding to the PAT-1 domain of lipid droplet coat proteins. J Biol Chem 2009; 284(46): 32116–32125PubMedCentralPubMedCrossRefGoogle Scholar
  134. 134.
    Chakrabarti P, Kim JY, Singh M, Shin YK, Kim J, Kumbrink J, Wu Y, Lee MJ, Kirsch KH, Fried SK, Kandror KV. Insulin inhibits lipolysis in adipocytes via the evolutionarily conserved mTORC1- Egr1-ATGL-mediated pathway. Mol Cell Biol 2013; 33(18): 3659–3666PubMedCentralPubMedCrossRefGoogle Scholar
  135. 135.
    Albert JS, Yerges-Armstrong LM, Horenstein RB, Pollin TI, Sreenivasan UT, Chai S, Blaner WS, Snitker S, O’Connell JR, Gong DW, Breyer RJ, Ryan AS, McLenithan JC, Shuldiner AR, Sztalryd C, Damcott CM. Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med 2014; 370 (24): 2307–2315PubMedCentralPubMedCrossRefGoogle Scholar
  136. 136.
    Gandotra S, Le Dour C, Bottomley W, Cervera P, Giral P, Reznik Y, Charpentier G, Auclair M, Delépine M, Barroso I, Semple RK, Lathrop M, Lascols O, Capeau J, O’Rahilly S, Magré J, Savage DB, Vigouroux C. Perilipin deficiency and autosomal dominant partial lipodystrophy. N Engl J Med 2011; 364(8): 740–748PubMedCentralPubMedCrossRefGoogle Scholar
  137. 137.
    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(40): 34998–35006PubMedCentralPubMedCrossRefGoogle Scholar
  138. 138.
    Schweiger M, Lass A, Zimmermann R, Eichmann TO, Zechner R. Neutral lipid storage disease: genetic disorders caused by mutations in adipose triglyceride lipase/PNPLA2 or CGI-58/ ABHD5. Am J Physiol Endocrinol Metab 2009; 297(2): E289–E296PubMedCrossRefGoogle Scholar
  139. 139.
    McLaughlin T, Abbasi F, Cheal K, Chu J, Lamendola C, Reaven G. Use of metabolic markers to identify overweight individuals who are insulin resistant. Ann Intern Med 2003; 139(10): 802–809PubMedCrossRefGoogle Scholar
  140. 140.
    McLaughlin T, Allison G, Abbasi F, Lamendola C, Reaven G. Prevalence of insulin resistance and associated cardiovascular disease risk factors among normal weight, overweight, and obese individuals. Metabolism 2004; 53(4): 495–499PubMedCrossRefGoogle Scholar
  141. 141.
    Stefan N, Kantartzis K, Machann J, Schick F, Thamer C, Rittig K, Balletshofer B, Machicao F, Fritsche A, Häring HU. Identification and characterization of metabolically benign obesity in humans. Arch Intern Med 2008; 168(15): 1609–1616PubMedCrossRefGoogle Scholar
  142. 142.
    Semple RK, Sleigh A, Murgatroyd PR, Adams CA, Bluck L, Jackson S, Vottero A, Kanabar D, Charlton-Menys V, Durrington P, Soos MA, Carpenter TA, Lomas DJ, Cochran EK, Gorden P, O’Rahilly S, Savage DB. Postreceptor insulin resistance contributes to human dyslipidemia and hepatic steatosis. J Clin Invest 2009; 119(2): 315–322PubMedCentralPubMedGoogle Scholar
  143. 143.
    Sanyal AJ, Chalasani N, Kowdley KV, McCullough A, Diehl AM, Bass NM, Neuschwander-Tetri BA, Lavine JE, Tonascia J, Unalp A, Van Natta M, Clark J, Brunt EM, Kleiner DE, Hoofnagle JH, Robuck PR; NASH CRN. Pioglitazone, vitamin E, or placebo for nonalcoholic steatohepatitis. N Engl J Med 2010; 362(18): 1675–1685PubMedCentralPubMedCrossRefGoogle Scholar
  144. 144.
    Calori G, Lattuada G, Piemonti L, Garancini MP, Ragogna F, Villa M, Mannino S, Crosignani P, Bosi E, Luzi L, Ruotolo G, Perseghin G. Prevalence, metabolic features, and prognosis of metabolically healthy obese Italian individuals: the Cremona Study. Diabetes Care 2011; 34(1): 210–215PubMedCentralPubMedCrossRefGoogle Scholar
  145. 145.
    Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab 2012; 97(7): 2482–2488PubMedCentralPubMedCrossRefGoogle Scholar
  146. 146.
    Lopez-Garcia E, Guallar-Castillon P, Leon-Muñoz L, Rodriguez-Artalejo F. Prevalence and determinants of metabolically healthy obesity in Spain. Atherosclerosis 2013; 231(1): 152–157PubMedCrossRefGoogle Scholar
  147. 147.
    Shea JL, Randell EW, Sun G. The prevalence of metabolically healthy obese subjects defined by BMI and dual-energy X-ray absorptiometry. Obesity (Silver Spring) 2011; 19(3): 624–630CrossRefGoogle Scholar
  148. 148.
    van Vliet-Ostaptchouk JV, Nuotio ML, Slagter SN, Doiron D, Fischer K, Foco L, Gaye A, Gögele M, Heier M, Hiekkalinna T, Joensuu A, Newby C, Pang C, Partinen E, Reischl E, Schwienbacher C, Tammesoo ML, Swertz MA, Burton P, Ferretti V, Fortier I, Giepmans L, Harris JR, Hillege HL, Holmen J, Jula A, Kootstra-Ros JE, Kvaløy K, Holmen TL, Männistö S, Metspalu A, Midthjell K, Murtagh MJ, Peters A, Pramstaller PP, Saaristo T, Salomaa V, Stolk RP, Uusitupa M, van der Harst P, van der Klauw MM, Waldenberger M, Perola M, Wolffenbuttel BH. The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. BMC Endocr Disord 2014; 14(1): 9PubMedCentralPubMedCrossRefGoogle Scholar
  149. 149.
    Durward CM, Hartman TJ, Nickols-Richardson SM. All-cause mortality risk of metabolically healthy obese individuals in NHANES III. J Obes 2012; 2012: 460321PubMedCentralPubMedCrossRefGoogle Scholar
  150. 150.
    Pajunen P, Kotronen A, Korpi-Hyövälti E, Keinänen-Kiukaanniemi S, Oksa H, Niskanen L, Saaristo T, Saltevo JT, Sundvall J, Vanhala M, Uusitupa M, Peltonen M. Metabolically healthy and unhealthy obesity phenotypes in the general population: the FIND2D Survey. BMC Public Health 2011; 11(1): 754PubMedCentralPubMedCrossRefGoogle Scholar
  151. 151.
    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 2012; 482(7384): 179–185PubMedCentralPubMedGoogle Scholar
  152. 152.
    Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol 2002; 16(5): 663–678PubMedCrossRefGoogle Scholar

Copyright information

© Higher Education Press and Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  1. 1.Department of Biochemistry and Molecular BiologyThird Military Medical UniversityChongqingChina
  2. 2.Department of Hepatobiliary Surgery, Daping Hospital & Institute of Surgery ResearchThird Military Medical UniversityChongqingChina
  3. 3.Department of Animal and Avian SciencesUniversity of MarylandCollege ParkUSA

Personalised recommendations