Molecular mechanisms of fatty liver in obesity

Lixia Gan, Wei Xiang, Bin Xie, Liqing Yu

PDF(451 KB)
PDF(451 KB)
Front. Med. ›› 2015, Vol. 9 ›› Issue (3) : 275-287. DOI: 10.1007/s11684-015-0410-2
REVIEW

Molecular mechanisms of fatty liver in obesity

Author information +
History +

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

Cite this article

Download citation ▾
Lixia Gan, Wei Xiang, Bin Xie, Liqing Yu. Molecular mechanisms of fatty liver in obesity. Front. Med., 2015, 9(3): 275‒287 https://doi.org/10.1007/s11684-015-0410-2

References

[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 Hepatol2005; 43(3): 508–514
CrossRef Pubmed Google scholar
[2]
Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol2013; 28(Suppl 1): 11–17
CrossRef Pubmed Google scholar
[3]
Masarone M, Federico A, Abenavoli L, Loguercio C, Persico M. Non alcoholic fatty liver: epidemiology and natural history. Rev Recent Clin Trials2014; 9(3): 126–133
CrossRef Pubmed Google scholar
[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. Hepatology2004; 40(6): 1387–1395
CrossRef Pubmed Google scholar
[5]
Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA2010; 303(3): 235–241
CrossRef Pubmed Google scholar
[6]
Schwimmer JB, Deutsch R, Kahen T, Lavine JE, Stanley C, Behling C. Prevalence of fatty liver in children and adolescents. Pediatrics2006; 118(4): 1388–1393
CrossRef Pubmed Google scholar
[7]
Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis2010; 28(1): 155–161
CrossRef Pubmed Google scholar
[8]
Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science2011; 332(6037): 1519–1523
CrossRef Pubmed Google scholar
[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 Metab2005; 288(2): E462–E468
CrossRef Pubmed Google scholar
[10]
Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res2011; 52(4): 593–617
CrossRef Pubmed Google scholar
[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. Gastroenterology2005; 129(1): 113–121
CrossRef Pubmed Google scholar
[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 Invest2005; 115(5): 1343–1351
CrossRef Pubmed Google scholar
[13]
Nielsen TS, Jessen N, Jørgensen JO, Møller N, Lund S. Dissecting adipose tissue lipolysis: molecular regulation and implications for metabolic disease. J Mol Endocrinol2014; 52(3): R199–R222
CrossRef Pubmed Google scholar
[14]
Redgrave TG. Formation of cholesteryl ester-rich particulate lipid during metabolism of chylomicrons. J Clin Invest1970; 49(3): 465–471
CrossRef Pubmed Google scholar
[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 Metab2010; 299(3): E384–E393
CrossRef Pubmed Google scholar
[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. Gastroenterology2006; 130(4): 1245–1258
CrossRef Pubmed Google scholar
[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. Biochemistry2013; 52(41): 7254–7261
CrossRef Pubmed Google scholar
[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. Diabetes2007; 56(12): 2863–2871
CrossRef Pubmed Google scholar
[19]
Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab2009; 20(2): 72–77
CrossRef Pubmed Google scholar
[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 Invest2011; 41(6): 642–651
CrossRef Pubmed Google scholar
[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. Science2006; 313(5793): 1628–1632
CrossRef Pubmed Google scholar
[22]
Furuhashi M, Hotamisligil GS. Fatty acid-binding proteins: role in metabolic diseases and potential as drug targets. Nat Rev Drug Discov2008; 7(6): 489–503
CrossRef Pubmed Google scholar
[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 ONE2012; 7(11): e48605
CrossRef Pubmed Google scholar
[24]
Berk PD. Regulatable fatty acid transport mechanisms are central to the pathophysiology of obesity, fatty liver, and metabolic syndrome. Hepatology2008; 48(5): 1362–1376
CrossRef Pubmed Google scholar
[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 Physiol2008; 294(5): G1281–G1287
CrossRef Pubmed Google scholar
[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. Gut2011; 60(10): 1394–1402
CrossRef Pubmed Google scholar
[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. Diabetes2007; 56(11): 2759–2765
CrossRef Pubmed Google scholar
[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): 239–250
Pubmed
[29]
Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest2006; 116(3): 607–614
CrossRef Pubmed Google scholar
[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 Int2010; 4(4): 741–748
CrossRef Pubmed Google scholar
[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. Gastroenterology2008; 134(2): 556–567
CrossRef Pubmed Google scholar
[32]
Memon RA, Tecott LH, Nonogaki K, Beigneux A, Moser AH, Grunfeld C, Feingold KR. Up-regulation of peroxisome proliferator-activated receptors (PPAR-α) and PPAR-γ messenger ribonucleic acid expression in the liver in murine obesity: troglitazone induces expression of PPAR-gamma-responsive adipose tissue-specific genes in the liver of obese diabetic mice. Endocrinology2000; 141(11): 4021–4031
Pubmed
[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 USA1999; 96(22): 12737–12742
CrossRef Pubmed Google scholar
[34]
Ishii S, Iizuka K, Miller BC, Uyeda K. Carbohydrate response element binding protein directly promotes lipogenic enzyme gene transcription. Proc Natl Acad Sci USA2004; 101(44): 15597–15602
CrossRef Pubmed Google scholar
[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 USA2001; 98(16): 9116–9121
CrossRef Pubmed Google scholar
[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 USA1998; 95(11): 5987–5992
CrossRef Pubmed Google scholar
[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 Chem1999; 274(50): 35832–35839
CrossRef Pubmed Google scholar
[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 USA1999; 96(24): 13656–13661
CrossRef Pubmed Google scholar
[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 USA1999; 96(20): 11235–11240
CrossRef Pubmed Google scholar
[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 Chem1997; 272(32): 20213–20221
CrossRef Pubmed Google scholar
[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. Cell2002; 110(4): 489–500
CrossRef Pubmed Google scholar
[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 USA2007; 104(16): 6519–6526
CrossRef Pubmed Google scholar
[43]
Yellaturu CR, Deng X, Cagen LM, Wilcox HG, Mansbach CM 2nd, 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 Chem2009; 284(12): 7518–7532
CrossRef Pubmed Google scholar
[44]
Horton JD, Goldstein JL, Brown MS. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. J Clin Invest2002; 109(9): 1125–1131
CrossRef Pubmed Google scholar
[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 Cell2000; 6(1): 77–86
CrossRef Pubmed Google scholar
[46]
Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science2008; 320(5882): 1492–1496
CrossRef Pubmed Google scholar
[47]
Lee JN, Ye J. Proteolytic activation of sterol regulatory element-binding protein induced by cellular stress through depletion of Insig-1. J Biol Chem2004; 279(43): 45257–45265
CrossRef Pubmed Google scholar
[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 Invest2009; 119(5): 1201–1215
CrossRef Pubmed Google scholar
[49]
Uyeda K, Repa JJ. Carbohydrate response element binding protein, ChREBP, a transcription factor coupling hepatic glucose utilization and lipid synthesis. Cell Metab2006; 4(2): 107–110
CrossRef Pubmed Google scholar
[50]
Ma L, Robinson LN, Towle HC. ChREBP*Mlx is the principal mediator of glucose-induced gene expression in the liver. J Biol Chem2006; 281(39): 28721–28730
CrossRef Pubmed Google scholar
[51]
Iizuka K, Horikawa Y. ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J2008; 55(4): 617–624
CrossRef Pubmed Google scholar
[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 J2006; 20(3): 434–443
CrossRef Pubmed Google scholar
[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 Genet2002; 31(1): 21–23
CrossRef Pubmed Google scholar
[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 Chem2007; 282(31): 22678–22688
CrossRef Pubmed Google scholar
[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 Metab2003; 29(5): 478–485
CrossRef Pubmed Google scholar
[56]
Gibbons GF, Wiggins D, Brown AM, Hebbachi AM. Synthesis and function of hepatic very-low-density lipoprotein. Biochem Soc Trans2004; 32(Pt 1): 59–64
CrossRef Pubmed Google scholar
[57]
Hussain MM, Shi J, Dreizen P. Microsomal triglyceride transfer protein and its role in apoB-lipoprotein assembly. J Lipid Res2003; 44(1): 22–32
CrossRef Pubmed Google scholar
[58]
Ginsberg HN, Fisher EA. The ever-expanding role of degradation in the regulation of apolipoprotein B metabolism. J Lipid Res2009; 50(Suppl): S162–S166
CrossRef Pubmed Google scholar
[59]
Kamagate A, Dong HH. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle2008; 7(20): 3162–3170
CrossRef Pubmed Google scholar
[60]
Tanoli T, Yue P, Yablonskiy D, Schonfeld G. Fatty liver in familial hypobetalipoproteinemia: roles of the APOB defects, intra-abdominal adipose tissue, and insulin sensitivity. J Lipid Res2004; 45(5): 941–947
CrossRef Pubmed Google scholar
[61]
Berriot-Varoqueaux N, Aggerbeck LP, Samson-Bouma M, Wetterau JR. The role of the microsomal triglygeride transfer protein in abetalipoproteinemia. Annu Rev Nutr2000; 20(1): 663–697
CrossRef Pubmed Google scholar
[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. Diabetes2002; 51(4): 1233–1239
CrossRef Pubmed Google scholar
[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 Med2011; 2(6): 1077–1081
Pubmed
[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. Hepatology2011; 54(1): 122–132
CrossRef Pubmed Google scholar
[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 Metab2006; 3(5): 309–319
CrossRef Pubmed Google scholar
[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 Res2013; 54(8): 2109–2120
CrossRef Pubmed Google scholar
[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 Genet2008; 40(12): 1461–1465
CrossRef Pubmed Google scholar
[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 Genet2012; 131(7): 1145–1152
CrossRef Pubmed Google scholar
[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. Hepatology2015; 61(1): 108–118
CrossRef Pubmed Google scholar
[70]
Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol2014; 7: 221–239
Pubmed
[71]
Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci2004; 1033(1): 17–29
CrossRef Pubmed Google scholar
[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 diet-induced metabolic disorders by enhancing fat oxidation. Cell Metab2008; 8(5): 347–358
CrossRef Pubmed Google scholar
[73]
Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature2006; 444(7121): 868–874
CrossRef Pubmed Google scholar
[74]
Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol2015; 62(3): 720–733
CrossRef Pubmed Google scholar
[75]
Rodgers JT, Puigserver P. Fasting-dependent glucose and lipid metabolic response through hepatic sirtuin 1. Proc Natl Acad Sci USA2007; 104(31): 12861–12866
CrossRef Pubmed Google scholar
[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 Metab2009; 9(4): 327–338
CrossRef Pubmed Google scholar
[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. Endocrinology2010; 151(6): 2504–2514
CrossRef Pubmed Google scholar
[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 J2011; 25(5): 1664–1679
CrossRef Pubmed Google scholar
[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 Chem2010; 285(44): 33959–33970
CrossRef Pubmed Google scholar
[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. Gastroenterology2014; 146(2): 539–49.e7
CrossRef Pubmed Google scholar
[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 Res2011; 52(9): 1693–1701
CrossRef Pubmed Google scholar
[82]
Gao Z, Zhang J, Kheterpal I, Kennedy N, Davis RJ, Ye J. Sirtuin 1 (SIRT1) protein degradation in response to persistent c-Jun N-terminal kinase 1 (JNK1) activation contributes to hepatic steatosis in obesity. J Biol Chem2011; 286(25): 22227–22234
CrossRef Pubmed Google scholar
[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 PPARalpha-mediated induction of fibroblast growth factor 21. Cell Metab2007; 5(6): 415–425
CrossRef Pubmed Google scholar
[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. Endocrinology2008; 149(12): 6018–6027
CrossRef Pubmed Google scholar
[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 Invest2005; 115(6): 1627–1635
CrossRef Pubmed Google scholar
[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-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci USA2009; 106(26): 10853–10858
CrossRef Pubmed Google scholar
[87]
Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr2010; 91(1): 254S–257S
CrossRef Pubmed Google scholar
[88]
Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med2002; 53(1): 409–435
CrossRef Pubmed Google scholar
[89]
Karpe F, Ehrenborg EE. PPARδ in humans: genetic and pharmacological evidence for a significant metabolic function. Curr Opin Lipidol2009; 20(4): 333–336
CrossRef Pubmed Google scholar
[90]
Musso G, Gambino R, Cassader M, Pagano G. A meta-analysis of randomized trials for the treatment of nonalcoholic fatty liver disease. Hepatology2010; 52(1): 79–104
CrossRef Pubmed Google scholar
[91]
Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol2013; 10(11): 676–685
CrossRef Pubmed Google scholar
[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 Med2007; 20(3): 351–358
Pubmed
[93]
Musso G, Gambino R, Cassader M. Recent insights into hepatic lipid metabolism in non-alcoholic fatty liver disease (NAFLD). Prog Lipid Res2009; 48(1): 1–26
CrossRef Pubmed Google scholar
[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 Int2009; 29(9): 1439–1446
CrossRef Pubmed Google scholar
[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. Gut2013; 62(11): 1625–1633
CrossRef Pubmed Google scholar
[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 Metab2010; 95(6): 2727–2735
CrossRef Pubmed Google scholar
[97]
Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol2013; 10(9): 542–552
CrossRef Pubmed Google scholar
[98]
Lagos-Quintana M, Rauhut R, Yalcin A, Meyer J, Lendeckel W, Tuschl T. Identification of tissue-specific microRNAs from mouse. Curr Biol2002; 12(9): 735–739
CrossRef Pubmed Google scholar
[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 Biol2004; 1(2): 106–113
CrossRef Pubmed Google scholar
[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 Metab2006; 3(2): 87–98
CrossRef Pubmed Google scholar
[101]
Krützfeldt J, Rajewsky N, Braich R, Rajeev KG, Tuschl T, Manoharan M, Stoffel M. Silencing of microRNAs in vivo with ‘antagomirs’. Nature2005; 438(7068): 685–689
CrossRef Pubmed Google scholar
[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. Gut2015; 64(5): 800–812.
CrossRef Pubmed Google scholar
[103]
Cheung 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. Hepatology2008; 48(6): 1810–1820
CrossRef Pubmed Google scholar
[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 Invest2012; 122(8): 2871–2883
CrossRef Pubmed Google scholar
[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 Invest2012; 122(8): 2884–2897
CrossRef Pubmed Google scholar
[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 Commun2013; 4: 2883
CrossRef Pubmed Google scholar
[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 Chem2010; 285(17): 12604–12611
CrossRef Pubmed Google scholar
[108]
Iliopoulos D, Drosatos K, Hiyama Y, Goldberg IJ, Zannis VI. MicroRNA-370 controls the expression of microRNA-122 and Cpt1α and affects lipid metabolism. J Lipid Res2010; 51(6): 1513–1523
CrossRef Pubmed Google scholar
[109]
Ou Z, Wada T, Gramignoli R, Li S, Strom SC, Huang M, Xie W. MicroRNA hsa-miR-613 targets the human LXRα gene and mediates a feedback loop of LXRα autoregulation. Mol Endocrinol2011; 25(4): 584–596
CrossRef Pubmed Google scholar
[110]
Singh R, Kaushik S, Wang Y, Xiang Y, Novak I, Komatsu M, Tanaka K, Cuervo AM, Czaja MJ. Autophagy regulates lipid metabolism. Nature2009; 458(7242): 1131–1135
CrossRef Pubmed Google scholar
[111]
Yang L, Li P, Fu S, Calay ES, Hotamisligil GS. Defective hepatic autophagy in obesity promotes ER stress and causes insulin resistance. Cell Metab2010; 11(6): 467–478
CrossRef Pubmed Google scholar
[112]
Lavallard VJ, Gual P. Autophagy and non-alcoholic fatty liver disease. Biomed Res Int 2014; 2014: 120179
[113]
Meijer AJ. Amino acid regulation of autophagosome formation. Methods Mol Biol2008; 445: 89–109
Pubmed
[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 Commun2011; 412(4): 618–625
CrossRef Pubmed Google scholar
[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 Res2014; 44(9): 1026–1036
CrossRef Pubmed Google scholar
[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 Hepatol2008; 6(12): 1396–1402
CrossRef Pubmed Google scholar
[117]
Johnson NA, George J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology2010; 52(1): 370–381
CrossRef Pubmed Google scholar
[118]
Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R. Lipolysis: pathway under construction. Curr Opin Lipidol2005; 16(3): 333–340
CrossRef Pubmed Google scholar
[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. Science2004; 306(5700): 1383–1386
CrossRef Pubmed Google scholar
[120]
Kraemer FB, Shen WJ. Hormone-sensitive lipase: control of intracellular tri-(di-)acylglycerol and cholesteryl ester hydrolysis. J Lipid Res2002; 43(10): 1585–1594
CrossRef Pubmed Google scholar
[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 Chem1997; 272(43): 27218–27223
CrossRef Pubmed Google scholar
[122]
Greenberg AS, Egan JJ, Wek SA, Garty NB, Blanchette-Mackie EJ, Londos C. Perilipin, a major hormonally regulated adipocyte-specific phosphoprotein associated with the periphery of lipid storage droplets. J Biol Chem1991; 266(17): 11341–11346
Pubmed
[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 Chem2004; 279(40): 42062–42071
CrossRef Pubmed Google scholar
[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 Chem2004; 279(29): 30490–30497
CrossRef Pubmed Google scholar
[125]
Granneman JG, Moore HP, Granneman RL, Greenberg AS, Obin MS, Zhu Z. Analysis of lipolytic protein trafficking and interactions in adipocytes. J Biol Chem2007; 282(8): 5726–5735
CrossRef Pubmed Google scholar
[126]
Granneman JG, Moore HP, Krishnamoorthy R, Rathod M. Perilipin controls lipolysis by regulating the interactions of AB-hydrolase containing 5 (Abhd5) and adipose triglyceride lipase (Atgl). J Biol Chem2009; 284(50): 34538–34544
CrossRef Pubmed Google scholar
[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 Metab2010; 11(3): 194–205
CrossRef Pubmed Google scholar
[128]
Wang Y, Zhang Y, Qian H, Lu J, Zhang Z, Min X, Lang M, Yang H, Wang N, Zhang P. The G0/G<?Pub Caret?>1 switch gene 2 is an important regulator of hepatic triglyceride metabolism. PLoS ONE2013; 8(8): e72315
CrossRef Pubmed Google scholar
[129]
Xu L, Zhou L, Li P. CIDE proteins and lipid metabolism. Arterioscler Thromb Vasc Biol2012; 32(5): 1094–1098
CrossRef Pubmed Google scholar
[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 Med2009; 1(5): 280–287
CrossRef Pubmed Google scholar
[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 USA2008; 105(22): 7833–7838
CrossRef Pubmed Google scholar
[132]
Shen WJ, Patel S, Miyoshi H, Greenberg AS, Kraemer FB. Functional interaction of hormone-sensitive lipase and perilipin in lipolysis. J Lipid Res2009; 50(11): 2306–2313
CrossRef Pubmed Google scholar
[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 Chem2009; 284(46): 32116–32125
CrossRef Pubmed Google scholar
[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 Biol2013; 33(18): 3659–3666
CrossRef Pubmed Google scholar
[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 3rd, 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 Med2014; 370(24): 2307–2315
CrossRef Pubmed Google scholar
[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 Med2011; 364(8): 740–748
CrossRef Pubmed Google scholar
[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 Chem2011; 286(40): 34998–35006
CrossRef Pubmed Google scholar
[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 Metab2009; 297(2): E289–E296
CrossRef Pubmed Google scholar
[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 Med2003; 139(10): 802–809
CrossRef Pubmed Google scholar
[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. Metabolism2004; 53(4): 495–499
CrossRef Pubmed Google scholar
[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 Med2008; 168(15): 1609–1616
CrossRef Pubmed Google scholar
[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 Invest2009; 119(2): 315–322
Pubmed
[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 Med2010; 362(18): 1675–1685
CrossRef Pubmed Google scholar
[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 Care2011; 34(1): 210–215
CrossRef Pubmed Google scholar
[145]
Hamer M, Stamatakis E. Metabolically healthy obesity and risk of all-cause and cardiovascular disease mortality. J Clin Endocrinol Metab2012; 97(7): 2482–2488
CrossRef Pubmed Google scholar
[146]
Lopez-Garcia E, Guallar-Castillon P, Leon-Muñoz L, Rodriguez-Artalejo F. Prevalence and determinants of metabolically healthy obesity in Spain. Atherosclerosis2013; 231(1): 152–157
CrossRef Pubmed Google scholar
[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): 624–630
CrossRef Pubmed Google scholar
[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 Disord2014; 14(1): 9
CrossRef Pubmed Google scholar
[149]
Durward CM, Hartman TJ, Nickols-Richardson SM. All-cause mortality risk of metabolically healthy obese individuals in NHANES III. J Obes 2012; 2012: 460321
[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 FIN-D2D Survey. BMC Public Health2011; 11(1): 754
CrossRef Pubmed Google scholar
[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. Nature2012; 482(7384): 179–185
Pubmed
[152]
Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol2002; 16(5): 663–678
CrossRef Pubmed Google scholar

Acknowledgements

This work was supported by funds from the National Natural Science Foundation of China [award numbers 81270482 (to L.G.) and 81372270 (to B.X.)] and the National Institutes of Health [award number R01DK085176 (to L.Y.)].
Compliance with ethics guidelines
Lixia Gan, Wei Xiang, Bin Xie, and Liqing Yu declare no conflict of interest. This manuscript is a review article and does not involve a research protocol requiring approval by the relevant institutional review board or ethics committee.

RIGHTS & PERMISSIONS

2014 Higher Education Press and Springer-Verlag Berlin Heidelberg
AI Summary AI Mindmap
PDF(451 KB)

Accesses

Citations

Detail

Sections
Recommended

/