Molecular mechanisms of fatty liver in obesity

Lixia Gan , Wei Xiang , Bin Xie , Liqing Yu

Front. Med. ›› 2015, Vol. 9 ›› Issue (3) : 275 -287.

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

Molecular mechanisms of fatty liver in obesity

Author information +
History +
PDF (451KB)

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 DOI:10.1007/s11684-015-0410-2

登录浏览全文

4963

注册一个新账户 忘记密码

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

[2]

Fan JG. Epidemiology of alcoholic and nonalcoholic fatty liver disease in China. J Gastroenterol Hepatol2013; 28(Suppl 1): 11–17

[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

[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

[5]

Flegal KM, Carroll MD, Ogden CL, Curtin LR. Prevalence and trends in obesity among US adults, 1999-2008. JAMA2010; 303(3): 235–241

[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

[7]

Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis2010; 28(1): 155–161

[8]

Cohen JC, Horton JD, Hobbs HH. Human fatty liver disease: old questions and new insights. Science2011; 332(6037): 1519–1523

[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

[10]

Hooper AJ, Adams LA, Burnett JR. Genetic determinants of hepatic steatosis in man. J Lipid Res2011; 52(4): 593–617

[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

[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

[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

[14]

Redgrave TG. Formation of cholesteryl ester-rich particulate lipid during metabolism of chylomicrons. J Clin Invest1970; 49(3): 465–471

[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

[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

[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

[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

[19]

Su X, Abumrad NA. Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol Metab2009; 20(2): 72–77

[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

[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

[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

[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

[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

[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

[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

[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

[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

[29]

Zelcer N, Tontonoz P. Liver X receptors as integrators of metabolic and inflammatory signaling. J Clin Invest2006; 116(3): 607–614

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[46]

Lee AH, Scapa EF, Cohen DE, Glimcher LH. Regulation of hepatic lipogenesis by the transcription factor XBP1. Science2008; 320(5882): 1492–1496

[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

[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

[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

[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

[51]

Iizuka K, Horikawa Y. ChREBP: a glucose-activated transcription factor involved in the development of metabolic syndrome. Endocr J2008; 55(4): 617–624

[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

[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

[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

[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

[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

[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

[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

[59]

Kamagate A, Dong HH. FoxO1 integrates insulin signaling to VLDL production. Cell Cycle2008; 7(20): 3162–3170

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[70]

Berlanga A, Guiu-Jurado E, Porras JA, Auguet T. Molecular pathways in non-alcoholic fatty liver disease. Clin Exp Gastroenterol2014; 7: 221–239

[71]

Jogl G, Hsiao YS, Tong L. Structure and function of carnitine acyltransferases. Ann N Y Acad Sci2004; 1033(1): 17–29

[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

[73]

Guarente L. Sirtuins as potential targets for metabolic syndrome. Nature2006; 444(7121): 868–874

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[87]

Kliewer SA, Mangelsdorf DJ. Fibroblast growth factor 21: from pharmacology to physiology. Am J Clin Nutr2010; 91(1): 254S–257S

[88]

Berger J, Moller DE. The mechanisms of action of PPARs. Annu Rev Med2002; 53(1): 409–435

[89]

Karpe F, Ehrenborg EE. PPARδ in humans: genetic and pharmacological evidence for a significant metabolic function. Curr Opin Lipidol2009; 20(4): 333–336

[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

[91]

Ratziu V. Pharmacological agents for NASH. Nat Rev Gastroenterol Hepatol2013; 10(11): 676–685

[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

[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

[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

[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

[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

[97]

Szabo G, Bala S. MicroRNAs in liver disease. Nat Rev Gastroenterol Hepatol2013; 10(9): 542–552

[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

[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

[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

[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

[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.

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[117]

Johnson NA, George J. Fitness versus fatness: moving beyond weight loss in nonalcoholic fatty liver disease. Hepatology2010; 52(1): 370–381

[118]

Zechner R, Strauss JG, Haemmerle G, Lass A, Zimmermann R. Lipolysis: pathway under construction. Curr Opin Lipidol2005; 16(3): 333–340

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[129]

Xu L, Zhou L, Li P. CIDE proteins and lipid metabolism. Arterioscler Thromb Vasc Biol2012; 32(5): 1094–1098

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[152]

Day CP. Pathogenesis of steatohepatitis. Best Pract Res Clin Gastroenterol2002; 16(5): 663–678

RIGHTS & PERMISSIONS

Higher Education Press and Springer-Verlag Berlin Heidelberg

AI Summary AI Mindmap
PDF (451KB)

4315

Accesses

0

Citation

Detail

Sections
Recommended

AI思维导图

/