Protective roles of adiponectin in obesityrelated fatty liver diseases: Mechanisms and therapeutic implications;Adiponectina e seu papel na proteção contra a doença hepática gordurosa na obesidade: Mecanismos e implicações terapêuticas

Arquivos Brasileiros de Endocrinologia e Metabologia

Volumn 53, Issue 2, 2009, Pages 201-212

  Wang, Yu ^a,b   Mingyan, Zhou ^a,b   Lam, Karen S L ^b,c   Xu, Aimin ^a,b,c  

^a Department of Pharmacology ^*  (Hong Kong)

^b UNIVERSITY OF HONG KONG   (Hong Kong)

^c UNIVERSITY OF HONG KONG   (Hong Kong)

Author keywords

Adiponectin; Hepatic steatosis; Insulin resistance; NASH

Indexed keywords

EID: 67649411827     PISSN: 00042730     EISSN: 16779487     Source Type: Journal    
DOI: 10.1590/S0004-27302009000200012     Document Type: Review

References (138)

1. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;346(16):1221-31.
2. Farrell GC. Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol. 2003;18(2):124-38.
3. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413-9.
4. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis to cirrhosis. Hepatology. 2006;43(2 Suppl 1): S99-S112.
5. Adams LA, Angulo P. Recent concepts in non-alcoholic fatty liver disease. Diabet Med. 2005;22(9):1129-33.
6. Ong JP, Pitts A, Younossi ZM. Increased overall mortality and liver-related mortality in non-alcoholic fatty liver disease. J Hepatol. 2008;49(4):608-12.
7. Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in non-alcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia. 2008;51(11):1947-53.
8. Watanabe S, Yaginuma R, Ikejima K, Miyazaki A. Liver diseases and metabolic syndrome. J Gastroenterol. 2008;43(7):509-18.
9. Machado M, Cortez-Pinto H. Non-alcoholic steatohepatitis and metabolic syndrome. Curr Opin Clin Nutr Metab Care. 2006;9(5):637-42.
10. Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middleaged Japanese men. Diabetes Care. 2007;30(11):2940-4.
11. Machado M, Cortez-Pinto H. Non-alcoholic fatty liver disease and insulin resistance. Eur J Gastroenterol Hepatol; 2005;17(8):823-6.
12. Mehta K, Van Thiel DH, Shah N, Mobarhan S. Nonalcoholic fatty liver disease: pathogenesis and the role of antioxidants. Nutr Rev. 2002;60(9):289-93.
13. Gastaldelli A, Cusi K, Pettiti M, Hardies J, Miyazaki Y, Berria R, et al. Relationship between hepatic/visceral fat and hepatic insulin resistance in nondiabetic and type 2 diabetic subjects. Gastroenterology. 2007;133(2):496-506.
14. Vuguin P, Raab E, Liu B, Barzilai N, Simmons R. Hepatic insulin resistance precedes the development of diabetes in a model of intrauterine growth retardation. Diabetes. 2004;53(10):2617-22.
15. Blaak EE. Fatty acid metabolism in obesity and type 2 diabetes mellitus. Proc Nutr Soc. 2003;62(3);753-60.
16. DeFronzo RA, Gunnarsson R, Björkman O, Olsson M, Wahren J. Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest. 1985;76(1):149-55.
17. Banerji MA, Buckley MC, Chaiken RL, Gordon D, Lebovitz HE, Kral JG. Liver fat, serum triglycerides and visceral adipose tissue in insulin-sensitive and insulin-resistant black men with NIDDM. Int J Obes Relat Metab Disord. 1995;19(12):846-50.
18. Holland WL, Brozinick JT, Wang LP, Hawkins ED, Sargent KM, Liu Y, et al. Inhibition of ceramide synthesis ameliorates glucocorticoid-, saturated-fat-, and obesity-induced insulin resistance. Cell Metab. 2007;5(3):167-79.
19. Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Am J Physiol Endocrinol Metab. 2003;285(4):E906-16.
20. Assimacopoulos-Jeannet F, Brichard S, Rencurel F, Cusin I, Jeanrenaud B. In vivo effects of hyperinsulinemia on lipogenic enzymes and glucose transporter expression in rat liver and adipose tissues. Metabolism. 1995;44(2):228-33.
21. Minehira K, Young SG, Villanueva CJ, Yetukuri L, Oresic M, Hellerstein MK, et al. Blocking VLDL secretion causes hepatic steatosis but does not affect peripheral lipid stores or insulin sensitivity in mice. J Lipid Res. 2008;49(9):2038-44.
22. Grefhorst A, Hoekstra J, Derks TG, Ouwens DM, Baller JF, Havinga R, et al. Acute hepatic steatosis in mice by blocking betaoxidation does not reduce insulin sensitivity of very-low-density lipoprotein production. Am J Physiol Gastrointest Liver Physiol. 2005;289(3):G592-8.
23. Dentin R, Benhamed F, Hainault I, Fauveau V, Foufelle F, Dyck JR, et al. Liver-specific inhibition of ChREBP improves hepatic steatosis and insulin resistance in ob/ob mice. Diabetes. 2006;55(8):2159-70.
24. Day CP, James OF. Steatohepatitis: a tale of two "hits"? Gastroenterology. 1998;114(4):842-5.
25. Brunt EM. Nonalcoholic steatohepatitis. Semin Liver Dis. 2004;24(1):3-20.
26. Charlton M. Noninvasive indices of fibrosis in NAFLD: starting to think about a three-hit (at least) phenomenon. Am J Gastroenterol. 2007;102(2):409-11.
27. de Luca C, Olefsky JM. Inflammation and insulin resistance. FEBS Lett. 2008;582(1):97-105.
28. Liou I, Kowdley KV. Natural history of nonalcoholic steatohepatitis. J Clin Gastroenterol. 2006;40 Suppl 1:S11-6.
29. Feldstein AE, Werneburg NW, Canbay A, Guicciardi ME, Bronk SF, Rydzewski R, et al. Free fatty acids promote hepatic lipotoxicity by stimulating TNF-alpha expression via a lysosomal pathway. Hepatology. 2004;40(1):185-94.
30. Jeong SK, Kim YK, Park JW, Shin YJ, Kim DS. Impact of visceral fat on the metabolic syndrome and nonalcoholic fatty liver disease. J Korean Med Sci. 2008;23(5):789-95.
31. van der Poorten D, Milner KL, Hui J, Hodge A, Trenell MI, Kench JG, et al. Visceral fat: a key mediator of steatohepatitis in metabolic liver disease. Hepatology. 2008;48(2):449-57.
32. Jakobsen MU, Berentzen T, Sørensen TI, Overvad K. Abdominal obesity and fatty liver. Epidemiol Rev. 2007;29:77-87.
33. Song HR, Yun KE, Park HS. Relation between alanine aminotransferase concentrations and visceral fat accumulation among nondiabetic overweight Korean women. Am J Clin Nutr. 2008;88(1):16-21.
34. Koda M, Kawakami M, Murawaki Y, Senda M. The impact of visceral fat in nonalcoholic fatty liver disease: cross-sectional and longitudinal studies. J Gastroenterol. 2007;42(11):897-903.
35. Gabriely I, Barzilai N. Surgical removal of visceral adipose tissue: effects on insulin action. Curr Diab Rep. 2003;3(3):201-6.
36. Antuna-Puente B, Feve B, Fellahi S, Bastard JP. Adipokines: the missing link between insulin resistance and obesity. Diabetes Metab. 2008;34(1):2-11.
37. Kamada Y, Takehara T, Hayashi N. Adipocytokines and liver disease. J Gastroenterol. 2008;43(11):811-22.
38. Tilg H, Hotamisligil GS. Nonalcoholic fatty liver disease: Cytokine-adipokine interplay and regulation of insulin resistance. Gastroenterology. 2006;131(3):934-45.
39. Javor ED, Ghany MG, Cochran EK, Oral EA, DePaoli AM, Premkumar A, et al. Leptin reverses nonalcoholic steatohepatitis in patients with severe lipodystrophy. Hepatology. 2005;41(4):753-60.
40. Javor ED, Cochran EK, Musso C, Young JR, Depaoli AM, Gorden P. Long-term efficacy of leptin replacement in patients with generalized lipodystrophy. Diabetes. 2005;54(7):1994-2002.
41. Huang XD, Fan Y, Zhang H, Wang P, Yuan JP, Li MJ, Zhan XY. Serum leptin and soluble leptin receptor in non-alcoholic fatty liver disease. World J Gastroenterol., 2008;14(18):2888-93.
42. Kim IK, Kim J, Kang JH, Song J. Serum Leptin as a Predictor of Fatty Liver in 7-Year-Old Korean Children. Ann Nutr Metab. 2008;53(2):109-16.
43. Marra F. Leptin and liver tissue repair: do rodent models provide the answers? J Hepatol. 2007;46(1):12-8.
44. Crespo J, Cayón A, Fernández-Gil P, Hernández-Guerra M, Mayorga M, Domínguez-Díez A, et al. Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Hepatology. 2001;34(6):1158-63.
45. Ribeiro PS, Cortez-Pinto H, Solá S, Castro RE, Ramalho RM, Baptista A, et al. Hepatocyte apoptosis, expression of death receptors, and activation of NF-kappaB in the liver of nonalcoholic and alcoholic steatohepatitis patients. Am J Gastroenterol. 2004;99(9):1708-17.
46. Younossi ZM, Jarrar M, Nugent C, Randhawa M, Afendy M, Stepanova M, et al. A novel diagnostic biomarker panel for obesity-related nonalcoholic steatohepatitis (NASH). Obes Surg. 2008;18(11):1430-7.
47. Li Z, Yang S, Lin H, Huang J, Watkins PA, Moser AB, et al. Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease. Hepatology. 2003;37(2):343-50.
48. Deng QG, She H, Cheng JH, French SW, Koop DR, Xiong S, Tsukamoto H. Steatohepatitis induced by intragastric overfeeding in mice. Hepatology. 2005;42(4):905-14.
49. Schnyder-Candrian S, Czarniecki J, Lerondel S, Corpataux J, Ryffel B, Schnyder B. Hepatic steatosis in the absence of tumor necrosis factor in mice. Cytokine. 2005;32(6):287-95.
50. Trujillo ME, Scherer PE. Adiponectin--journey from an adipocyte secretory protein to biomarker of the metabolic syndrome. J Intern Med. 2005;257(2):167-75.
51. Lopez-Bermejo A, Botas-Cervero P, Ortega-Delgado F, Delgado E, García-Gil MM, Funahashi T, et al. Adiponectin, hepatocellular dysfunction and insulin sensitivity. Clin Endocrinol (Oxf). 2004;60(2):256-63.
52. Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-alpha or adiponectin?Hepatology. 2004;40(1):46-54.
53. Shimada M, Kawahara H, Ozaki K, Fukura M, Yano H, Tsuchishima M, et al. Usefulness of a combined evaluation of the serum adiponectin level, HOMA-IR, and serum type IV collagen 7S level to predict the early stage of nonalcoholic steatohepatitis. Am J Gastroenterol. 2007;102(9):1931-8.
54. Musso G, Gambino R, Biroli G, Carello M, Fagà E, Pacini G, et al. Hypoadiponectinemia predicts the severity of hepatic fibrosis and pancreatic Beta-cell dysfunction in nondiabetic nonobese patients with nonalcoholic steatohepatitis. Am J Gastroenterol. 2005;100(11):2438-46.
55. Aygun C, Senturk O, Hulagu S, Uraz S, Celebi A, Konduk T, et al. Serum levels of hepatoprotective peptide adiponectin in non-alcoholic fatty liver disease. Eur J Gastroenterol Hepatol. 2006;18(2):175-80.
56. Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, et al. Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. J Clin Endocrinol Metab. 2004;89(1):200-6.
57. Ikejima K, Okumura K, Kon K, Takei Y, Sato N. Role of adipocytokines in hepatic fibrogenesis. J Gastroenterol Hepatol. 2007;22 Suppl 1:S87-92.
58. Kamada Y, Tamura S, Kiso S, Matsumoto H, Saji Y, Yoshida Y, et al. Enhanced carbon tetrachloride-induced liver fibrosis in mice lacking adiponectin. Gastroenterology. 2003;125(6):1796-807.
59. Masaki T, Chiba S, Tatsukawa H, Yasuda T, Noguchi H, Seike M, Yoshimatsu H. Adiponectin protects LPS-induced liver injury through modulation of TNF-alpha in KK-Ay obese mice. Hepatology. 2004;40(1):177-84.
60. Matsumoto H, Tamura S, Kamada Y, Kiso S, Fukushima J, Wada A, et al. Adiponectin deficiency exacerbates lipopolysaccharide/D-galactosamine-induced liver injury in mice. World J Gastroenterol. 2006;12(21):3352-8.
61. Thakur V, Pritchard MT, McMullen MR, Nagy LE. Adiponectin normalizes LPS-stimulated TNF-alpha production by rat Kupffer cells after chronic ethanol feeding. Am J Physiol Gastrointest Liver Physiol. 2006;290(5):G998-1007.
62. Xu A, Wang Y, Keshaw H, Xu LY, Lam KS, Cooper GJ. The fat-derived hormone adiponectin alleviates alcoholic and nonalcoholic fatty liver diseases in mice. J Clin Invest. 2003;112(1):91-100.
63. Kamada Y, Matsumoto H, Tamura S, Fukushima J, Kiso S, Fukui K, et al. Hypoadiponectinemia accelerates hepatic tumor formation in a nonalcoholic steatohepatitis mouse model. J Hepatol. 2007;47:556-64.
64. Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific gene dysregulated in obesity. J Biol Chem. 1996;271:10697-703.
65. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cDNA cloning and expression of a novel adipose specific collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun. 1996;221:286-9.
66. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem. 1996;120:803-12.
67. Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel serum protein similar to C1q, produced exclusively in adipocytes. J Biol Chem. 1995;270:26746-9.
68. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116:1784-92.
69. Lam KS, Xu A. Adiponectin: protection of the endothelium. Curr Diab Rep. 2005;5:254-9.
70. Yamauchi T, Hara K, Kubota N, Terauchi Y, Tobe K, Froguel P, et al. Dual roles of adiponectin/Acrp30 in vivo as an anti-diabetic and anti-atherogenic adipokine. Curr Drug Targets Immune Endocr Metabol Disord. 2003;3:243-54.
71. Zhu W, Cheng KK, Vanhoutte PM, Lam KS, Xu A. Vascular effects of adiponectin: molecular mechanisms and potential therapeutic intervention. Clin Sci (Lond). 2008;114:361-74.
72. Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab. 2007;9:282-9.
73. Wang Y, Lam KS, Yau MH, Xu A. Post-translational modifications of adiponectin: mechanisms and functional implications. Biochem J. 2008;409:623-33.
74. Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization state-dependent activation of NF-kappa B signaling pathway by adipocyte complement-related protein of 30 kDa (Acrp30). J Biol Chem. 2002;277:29359-62.
75. Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB, et al. Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity. Different oligomers activate different signal transduction pathways. J Biol Chem. 2003;278:50810-7.
76. Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, et al. Impaired multimerization of human adiponectin mutants associated with diabetes. Molecular structure and multimer formation of adiponectin. J Biol Chem. 2003;278:40352-63.
77. Xu A, Chan KW, Hoo RL, Wang Y, Tan KC, Zhang J, et al. Testosterone selectively reduces the high molecular weight form of adiponectin by inhibiting its secretion from adipocytes. J Biol Chem. 2005;280:18073-80.
78. Richards AA, Stephens T, Charlton HK, Jones A, Macdonald GA, Prins JB, Whitehead JP. Adiponectin multimerization is dependent on conserved lysines in the collagenous domain: evidence for regulation of multimerization by alterations in posttranslational modifications. Mol Endocrinol. 2006;20:1673-87.
79. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T et al. Structure-function studies of the adipocyte-secreted hormone Acrp30/adiponectin. Implications fpr metabolic regulation and bioactivity. J Biol Chem. 2003;278:9073-85.
80. Wang Y, Xu A, Knight C, Xu LY, Cooper GJ. Hydroxylation and glycosylation of the four conserved lysine residues in the collagenous domain of adiponectin. Potential role in the modulation of its insulin-sensitizing activity. J Biol Chem. 2002;277:19521-9.
81. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004;279:12152-62.
82. Suzuki S, Wilson-Kubalek EM, Wert D, Tsao TS, Lee DH. The oligomeric structure of high molecular weight adiponectin. FEBS Lett. 2007;581:809-14.
83. Radjainia M, Wang Y, Mitra AK. Structural polymorphism of oligomeric adiponectin visualized by electron microscopy. J Mol Biol. 2008;381:419-30.
84. Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert MO, et al. Changes of adiponectin oligomer composition by moderate weight reduction. Diabetes. 2005;54:2712-9.
85. Salani B, Briatore L, Andraghetti G, Adami GF, Maggi D, Cordera R. High-molecular weight adiponectin isoforms increase after biliopancreatic diversion in obese subjects. Obesity (Silver Spring). 2006;14:1511-4.
86. Swarbrick MM, Austrheim-Smith IT, Stanhope KL, Van Loan MD, Ali MR, Wolfe BM et al. Circulating concentrations of high-molecular-weight adiponectin are increased following Roux-en-Y gastric bypass surgery. Diabetologia. 2006;49:2552-8.
87. Liu Y, Retnakaran R, Hanley A, Tungtrongchitr R, Shaw C, Sweeney G. Total and high molecular weight but not trimeric or hexameric forms of adiponectin correlate with markers of the metabolic syndrome and liver injury in Thai subjects. J Clin Endocrinol Metab. 2007;92:4313-8.
88. Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-secreted protein Acrp30 enhances hepatic insulin action. Nat Med. 2001;7:947-53.
89. Wang Y, Lam KS, Chan L, Chan KW, Lam JB, Lam MC, et al. Posttranslational modifications of the four conserved lysine residues within the collagenous domain of adiponectin are required for the formation of its high molecular weight oligomeric complex. J Biol Chem. 2006;281:16391-400.
90. Kubota N, Terauchi Y, Kubota T, Kumagai H, Itoh S, Satoh H, et al. Pioglitazone ameliorates insulin resistance and diabetes by both adiponectin-dependent and -independent pathways. J Biol Chem. 2006;281:8748-55.
91. Nawrocki AR, Rajala MW, Tomas E, Pajvani UB, Saha AK, Trumbauer ME, et al. Mice lacking adiponectin show decreased hepatic insulin sensitivity and reduced responsiveness to peroxisome proliferator-activated receptor gamma agonists. J Biol Chem. 2006;281:2654-60.
92. Wang Y, Lu G, Wong WP, Vliegenthart JF, Gerwig GJ, Lam KS, et al. Proteomic and functional characterization of endogenous adiponectin purified from fetal bovine serum. Proteomics. 2004;4:3933-42.
93. Neumeier M, Sigruener A, Eggenhofer E, Weigert J, Weiss TS, Schaeffler A, et al. High molecular weight adiponectin reduces apolipoprotein B and E release in human hepatocytes. Biochem Biophys Res Commun. 2007;352:543-8.
94. Adachi M, Brenner DA. High molecular weight adiponectin inhibits proliferation of hepatic stellate cells via activation of adenosine monophosphate-activated protein kinase. Hepatology. 2008;47:677-85.
95. Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors. Endocr Rev. 2005;26:439-51.
96. Kadowaki T, Yamauchi T, Kubota N. The physiological and pathophysiological role of adiponectin and adiponectin receptors in the peripheral tissues and CNS. FEBS Lett. 2008;582:74-80.
97. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med. 2007;13:332-9.
98. Liu Y, Michael MD, Kash S, Bensch WR, Monia BP, Murray SF, et al. Deficiency of adiponectin receptor 2 reduces diet-induced insulin resistance but promotes type 2 diabetes. Endocrinology. 2007;148:683-92.
99. Kaser S, Moschen A, Cayon A, Kaser A, Crespo J, Pons-Romero F, et al. Adiponectin and its receptors in non-alcoholic steatohepatitis. Gut. 2005;54:117-21.
100. Nannipieri M, Cecchetti F, Anselmino M, Mancini E, Marchetti G, Bonotti A, et al. Pattern of expression of adiponectin receptors in human liver and its relation to nonalcoholic steatohepatitis. Obes Surg. 2008;oct 16 [Epub ahead of print].
101. Uribe M, Zamora-Valdés D, Moreno-Portillo M, Bermejo-Martínez L, Pichardo-Bahena R, Baptista-González HA, et al. Hepatic expression of ghrelin and adiponectin and their receptors in patients with nonalcoholic fatty liver disease. Ann Hepatol. 2008;7:67-71.
102. Vuppalanchi R, Marri S, Kolwankar D, Considine RV, Chalasani N. Is adiponectin involved in the pathogenesis of nonalcoholic steatohepatitis? A preliminary human study. J Clin Gastroenterol. 2005;39:237-42.
103. Cheng KK, Lam KS, Wang Y, Huang Y, Carling D, Wu D, et al. Adiponectin-induced endothelial nitric oxide synthase activation and nitric oxide production are mediated by APPL1 in endothelial cells. Diabetes. 2007;56:1387-94.
104. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, et al. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med. 2002;8:1288-95.
105. Shibata R, Ouchi N, Ito M, Kihara S, Shiojima I, Pimentel DR, et al. Adiponectin-mediated modulation of hypertrophic signals in the heart. Nat Med. 2004;10:1384-9.
106. Kubota N, Yano W, Kubota T, Yamauchi T, Itoh S, Kumagai H, et al. Adiponectin stimulates AMP-activated protein kinase in the hypothalamus and increases food intake. Cell Metab. 2007;6:55-68.
107. Mao X, Kikani CK, Riojas RA, Langlais P, Wang L, Ramos FJ, et al. APPL1 binds to adiponectin receptors and mediates adiponectin signalling and function. Nat Cell Biol. 2006;8:516-23.
108. Chandrasekar B, Boylston WH, Venkatachalam K, Webster NJ, Prabhu SD, Valente AJ. Adiponectin blocks interleukin-18-mediated endothelial cell death via APPL1-dependent AMP-activated protein kinase (AMPK) activation and IKK/NF-kappaB/PTEN suppression. J Biol Chem. 2008;283:24889-98.
109. Saito T, Jones CC, Huang S, Czech MP, Pilch PF. The interaction of Akt with APPL1 is required for insulin-stimulated Glut4 translocation. J Biol Chem. 2007;282:32280-7.
110. Woods A, Azzout-Marniche D, Foretz M, Stein SC, Lemarchand P, Ferré P, et al. Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. Mol Cell Biol. 2000;20:6704-11.
111. Tomita K, Tamiya G, Ando S, Kitamura N, Koizumi H, Kato S, et al. AICAR, an AMPK activator, has protective effects on alcohol-induced fatty liver in rats. Alcohol Clin Exp Res. 2005;29 Suppl12:240S-5S.
112. You M, Considine RV, Leone TC, Kelly DP, Crabb DW. Role of adiponectin in the protective action of dietary saturated fat against alcoholic fatty liver in mice. Hepatology. 2005;42:568-77.
113. Carter-Kent C, Zein NN, Feldstein AE. Cytokines in the pathogenesis of fatty liver and disease progression to steatohepatitis: implications for treatment. Am J Gastroenterol. 2008;103:1036-42.
114. Choi KM, Ryu OH, Lee KW, Kim HY, Seo JA, Kim SG, et al. Serum adiponectin, interleukin-10 levels and inflammatory markers in the metabolic syndrome. Diabetes Res Clin Pract. 2007;75:235-40.
115. Engeli S, Feldpausch M, Gorzelniak K, Hartwig F, Heintze U, Janke J, et al. Association between adiponectin and mediators of inflammation in obese women. Diabetes. 2003;52:942-7.
116. Park PH, Thakur V, Pritchard MT, McMullen MR, Nagy LE. Regulation of Kupffer cell activity during chronic ethanol exposure: role of adiponectin. J Gastroenterol Hepatol. 2006;21 Suppl 3:S30-3.
117. Zhou M, Xu A, Tam PK, Lam KS, Chan L, Hoo RL, et al. Mitochondrial dysfunction contributes to the increased vulnerabilities of adiponectin knockout mice to liver injury. Hepatology. 2008;48:1087-96.
118. Choi S, Diehl AM. Role of inflammation in nonalcoholic steatohepatitis. Curr Opin Gastroenterol. 2005;21:702-7.
119. Jarrar MH, Baranova A, Collantes R, Ranard B, Stepanova M, Bennett C, et al. Adipokines and cytokines in non-alcoholic fatty liver disease. Aliment Pharmacol Ther. 2008;27:412-21.
120. Wulster-Radcliffe MC, Ajuwon KM, Wang J, Christian JA, Spurlock ME. Adiponectin differentially regulates cytokines in porcine macrophages. Biochem Biophys Res Commun. 2004;316:924-9.
121. Kumada M, Kihara S, Ouchi N, Kobayashi H, Okamoto Y, Ohashi K, et al. Adiponectin specifically increased tissue inhibitor of metalloproteinase-1 through interleukin-10 expression in human macrophages. Circulation. 2004;109:2046-9.
122. Wolf AM, Wolf D, Rumpold H, Enrich B, Tilg H. Adiponectin induces the anti-inflammatory cytokines IL-10 and IL-1RA in human leukocytes. Biochem Biophys Res Commun. 2004;323:630-5.
123. Yamaguchi N, Argueta JG, Masuhiro Y, Kagishita M, Nonaka K, Saito T, et al. Adiponectin inhibits Toll-like receptor family-induced signaling. FEBS Lett. 2005;579:6821-6.
124. Bertolani C, Marra F. The role of adipokines in liver fibrosis. Pathophysiology. 2008;15:91-101.
125. Ding X, Saxena NK, Lin S, Xu A, Srinivasan S, Anania FA. The roles of leptin and adiponectin: a novel paradigm in adipocytokine regulation of liver fibrosis and stellate cell biology. Am J Pathol. 2005;166:1655-69.
126. Caligiuri A, Bertolani C, Guerra CT, Aleffi S, Galastri S, Trappoliere M, et al. Adenosine monophosphate-activated protein kinase modulates the activated phenotype of hepatic stellate cells. Hepatology. 2008;47:668-76.
127. Tomita K, Oike Y, Teratani T, Taguchi T, Noguchi M, Suzuki T, et al. Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice. Hepatology. 2008;48:458-73.
128. Parish R, Petersen KF. Mitochondrial dysfunction and type 2 diabetes. Curr Diab Rep. 2005;5:177-83.
129. Perez-Carreras M, Del Hoyo P, Martín MA, Rubio JC, Martín A, Castellano G, et al. Defective hepatic mitochondrial respiratory chain in patients with nonalcoholic steatohepatitis. Hepatology. 2003;38:999-1007.
130. Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183-92.
131. Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D. The ins and outs of mitochondrial dysfunction in NASH. Diabetes Metab. 2004;30:121-38.
132. Negre-Salvayre A, Hirtz C, Carrera G, Cazenave R, Troly M, Salvayre R, et al. A role for uncoupling protein-2 as a regulator of mitochondrial hydrogen peroxide generation. FASEB J. 1997;11:809-15.
133. Bai Y, Onuma H, Bai X, Medvedev AV, Misukonis M, Weinberg JB, et al. Persistent nuclear factor-kappa B activation in Ucp2-/-mice leads to enhanced nitric oxide and inflammatory cytokine production. J Biol Chem. 2005;280:19062-9.
134. Baffy G. Uncoupling protein-2 and non-alcoholic fatty liver disease. Front Biosci. 2005;10:2082-96.
135. Petersen KF, Dufour S, Befroy D, Lehrke M, Hendler RE, Shulman GI. Reversal of nonalcoholic hepatic steatosis, hepatic insulin resistance, and hyperglycemia by moderate weight reduction in patients with type 2 diabetes. Diabetes. 2005;54:603-8.
136. Dixon JB, Bhathal PS, Hughes NR, O'Brien PE. Nonalcoholic fatty liver disease: Improvement in liver histological analysis with weight loss. Hepatology. 2004;39:1647-54.
137. Angulo P. Current best treatment for non-alcoholic fatty liver disease. Expert Opin Pharmacother. 2003;4:611-23.
138. Xu A, Wang H, Hoo RL, Sweeney G, Vanhoutte PM, Wang Y, et al. Selective elevation of adiponectin production by the natural compounds derived from a medicinal herb alleviates insulin resistance and glucose intolerance in obese mice. Endocrinology. 2009;150:625-33.