| | Amelioration of high fat diet induced liver lipogenesis and hepatic steatosis by interleukin-22Received 9 October 2009; received in revised form 26 February 2010; accepted 1 March 2010. published online 21 April 2010. Background & AimsInterleukin-22 (IL-22) is a Th17-related cytokine within the IL-10 family and plays an important role in host defense and inflammatory responses in orchestration with other Th17 cytokines. IL-22 exerts its functions in non-immune cells as its functional receptor IL-22R1 is restricted in peripheral tissues but not in immune cells. It was recently found that IL-22 serves as a protective molecule to counteract the destructive nature of the T cell-mediated immune response to liver damage. However, it is currently unknown whether IL-22 has an effect on lipid metabolism in the liver. MethodsIn this study, we demonstrate that IL-22 alleviates hepatic steatosis induced by high fat diet (HFD). ResultsAdministration of recombinant murine IL-22 (rmIL-22) was able to stimulate STAT3 phosphorylation in HepG2 cells and mouse liver. The activation of STAT3 by rmIL-22 was reduced by the over-expression of a dominant negative IL-22R1. Within hours after rmIL-22 treatment, the expression of lipogenesis-related genes including critical transcription factors and enzymes for lipid synthesis in the liver was significantly down-regulated. The levels of triglyceride and cholesterol in the liver were significantly reduced by long-term treatment of rmIL-22 in C57BL/6 and ob/ob mice fed with HFD. The HFD-induced increases of ALT and AST in ob/ob mice were ameliorated by rmIL-22 treatment. In addition, the expression of fatty acid synthase and TNF-α in the liver was decreased by long-term rmIL-22 administration. ConclusionsCollectively, these data indicate that IL-22, in addition to its known functions in host defense and inflammation, has a protective role in HFD-induced hepatic steatosis via its regulation on lipid metabolism in the liver. Abbreviations: aa, amino acid, ACC1, acetyl-CoA carboxylase, ACLY, ATP citrate lyase, ALT, alanine aminotransferase, AST, aspartate aminotransferase, ChREBP, MLX interacting protein-like, CYP7A1, cytochrome P450, family 7, subfamily a, polypeptide 1, DGAT1/2, diacylglycerol O-acyltransferase homolog 1/2, ELOVL6, ELOVL family member 6, elongation of long chain fatty acids, FAS, fatty acid synthase, HMGCR, 3-hydroxy-3-methylglutaryl-coenzyme A reductase, GPAM, glycerol-3-phosphate acyltransferase, mitochondrial, HFD, high fat diet, HE, Hematoxylin–Eosin, IL-22, interleukin 22, ND, normal chow diet, PEI, polyethylenimine, LXRα, nuclear receptor subfamily 1, LXRβ, nuclear receptor subfamily 1, group H, member 2, PVDF, polyvinylidene fluoride, PPARαβ, peroxisome proliferator-activated receptor αβ, rmIL-22, recombinant murine IL-22, RT-PCR, reverse transcription PCR, RIPA, radioimmunoprecipitation assay, STAT3, signal transducer and activator of transcription 3, SOCS3, suppressor of cytokine signaling 3, SREBP-1c, sterol regulatory element binding transcription factor 1C, SCD1, stearoyl-coenzyme A desaturase 1, TNF-α, tumor necrosis factor α 1 Key Laboratory of Nutrition and Metabolism, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Graduate School of the Chinese Academy of Sciences, Shanghai 200031, China 2 Generon Corporation, Building 9, 720 Cai Lun Road, Zhang Jiang Hi-Tech Park, Shanghai 201203, China  Corresponding author. Address: Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 294 Taiyuan Rd., Shanghai 200031, China. Tel.: +86 21 54920916; fax: +86 21 54920291.
PII: S0168-8278(10)00264-3 doi:10.1016/j.jhep.2010.03.004 © 2010 European Association for the Study of the Liver. Published by Elsevier Inc. All rights reserved. | |
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