Inflammation-associated interleukin-6/signal transducer and ... : Hepatology (original) (raw)

Steatohepatitis/Metabolic Liver Disease

Inflammation-associated interleukin-6/signal transducer and activator of transcription 3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in interleukin-10–deficient mice

Miller, Andrew M.1; Wang, Hua1; Bertola, Adeline1; Park, Ogyi1; Horiguchi, Norio1,2; Ki, Sung Hwan1,3; Yin, Shi1,4; Lafdil, Fouad1,5,6; Gao, Bin1,*

1_Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, MD_

2_Department of Medicine and Molecular Science, Gunma University Graduate School of Medicine, Gunma, Japan_

3_Laboratory of Toxicology, College of Pharmacy, Chosun University, Gwangju, South Korea_

4_Institute of Clinical Pharmacology, Anhui Medical University, Hefei, Anhui, China_

5_INSERM, U955, Créteil, France_

6_University of Paris, East Créteil, France_

*Address reprint requests to: Laboratory of Liver Diseases, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 5625 Fishers Lane, Bethesda, MD 20892

Email: [email protected]

Received 23 March 2011; accepted 13 June 2011

Grant sponsor: intramural program of the National Institute on Alcohol Abuse and Alcoholism; Grant sponsor: National Institutes of Health.

Potential conflict of interest: Nothing to report.

Supported by the intramural program of the National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health.

These authors contributed equally to this work.

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Additional Supporting Information may be found in the online version of this article.

Abstract

Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, whereas inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin (IL)-10, a key anti-inflammatory cytokine, exacerbates liver inflammation, steatosis, and hepatocellular damage in alcoholic and nonalcoholic fatty liver disease models that were achieved via feeding mice with a liquid diet containing 5% ethanol for 4 weeks or a high-fat diet (HFD) for 12 weeks, respectively. IL-10 knockout (IL-10−/−) mice and several other strains of genetically modified mice were generated and used. Compared with wild-type mice, IL-10−/− mice had greater liver inflammatory response with higher levels of IL-6 and hepatic signal transducer and activator of transcription 3 (STAT3) activation, but less steatosis and hepatocellular damage after alcohol or HFD feeding. An additional deletion of IL-6 or hepatic STAT3 restored steatosis and hepatocellular damage but further enhanced liver inflammatory response in IL-10−/− mice. In addition, the hepatic expression of sterol regulatory element-binding protein 1 and key downstream lipogenic proteins and enzymes in fatty acid synthesis were down-regulated in IL-10−/− mice. Conversely, IL-10−/− mice displayed enhanced levels of phosphorylated adenosine monophosphate-activated protein kinase and its downstream targets including phosphorylated acetyl-coenzyme A carboxylase and carnitine palmitoyltransferase 1 in the liver. Such dysregulations were corrected in IL-10−/−IL-6−/− or IL-10−/−STAT3Hep−/− double knockout mice. Conclusion: IL-10−/− mice are prone to liver inflammatory response but are resistant to steatosis and hepatocellular damage induced by ethanol or HFD feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently down-regulates lipogenic genes but up-regulates fatty acid oxidation-associated genes in the liver. (HEPATOLOGY 2011; 54:846–856)

Abbreviations: ACC1, acetyl-coenzyme A carboxylase; ALT, alanine aminotransferase; AMPK, adenosine monophosphate-activated protein kinase; ASH, alcoholic steatohepatitis; CPT-1, carnitine palmitoyltransferase 1; dKO, double knockout; ETOH, ethanol; FAS, fatty acid synthase; HFD, high-fat diet; IFN-γ, interferon-γ; IL, interleukin; mRNA, messenger RNA; NASH, nonalcoholic steatohepatitis; pACC1, phosphorylated ACC1; pAMPK, phosphorylated AMPK; pSTAT3, phosphorylated STAT3; SREBP-1c, sterol regulatory element-binding protein 1; STAT3, signal transducer and activator of transcription 3; STD, standard diet; TNF-α, tumor necrosis factor α; WT, wild-type.