Our laboratory has been actively studying the molecular mechanisms of alcoholic liver disease, focusing on the role of interleukin-6 (IL-6) and IL-10 and their downstream signal STAT3 in alcoholic fatty liver and liver inflammation Inflammation-associated IL-6/STAT3 activation ameliorates alcoholic and nonalcoholic fatty liver diseases in IL-10 deficient mice. Alcoholic and nonalcoholic steatohepatitis are characterized by fatty liver plus inflammation. It is generally believed that steatosis promotes inflammation, while inflammation in turn aggregates steatosis. Thus, we hypothesized the deletion of interleukin-10 (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 for 12 weeks, respectively. IL-10 knockout (IL-10(-/-) ) mice and several other strains of genetically modified mice were generated and used. Compared to 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 high fat diet 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 SREBP1c and key downstream lipogenic proteins and enzymes in fatty acid synthesis were downregulated in IL-10(-/-) mice. Conversely, IL-10(-/-) mice displayed enhanced levels of phosphorylated AMPK and its downstream targets including phosphorylated ACC1 and CPT-1 in the liver. Such dysregulations were corrected in IL-10(-/-) IL-6(-/-) or IL-10(-/-) STAT3(Hep-/-) double knockout mice. In conclusion, IL-10(-/-) mice are prone to liver inflammatory response but resistant to steatosis and hepatocellular damage induced by ethanol or high fat diet feeding. Resistance to steatosis in these mice is attributable to elevation of inflammation-associated hepatic IL-6/STAT3 activation that subsequently downregulates lipogenic genes but upregulates fatty acid oxidation-associated genes in the liver In addition, we are also collaborating with Drs. George Kunos and Pal Pacher from NIAAA to investigate the role of the endocannabinoid system in alcoholic liver disease.

Project Start
Project End
Budget Start
Budget End
Support Year
10
Fiscal Year
2011
Total Cost
$1,033,768
Indirect Cost
Name
National Institute on Alcohol Abuse and Alcoholism
Department
Type
DUNS #
City
State
Country
Zip Code
Chen, Hanqing; Shen, Feng; Sherban, Alex et al. (2018) DEP domain-containing mTOR-interacting protein suppresses lipogenesis and ameliorates hepatic steatosis and acute-on-chronic liver injury in alcoholic liver disease. Hepatology 68:496-514
Guillot, Adrien; Gasmi, Imène; Brouillet, Arthur et al. (2018) Interleukins-17 and 27 promote liver regeneration by sequentially inducing progenitor cell expansion and differentiation. Hepatol Commun 2:329-343
Li, Hongjie; Feng, Dechun; Cai, Yan et al. (2018) Hepatocytes and neutrophils cooperatively suppress bacterial infection by differentially regulating lipocalin-2 and neutrophil extracellular traps. Hepatology 68:1604-1620
Jiang, Yiming; Feng, Dechun; Ma, Xiaochao et al. (2018) Pregnane X Receptor Regulates Liver Size and Liver Cell Fate via Yes-associated Protein Activation. Hepatology :
Ouyang, Xinshou; Han, Sheng-Na; Zhang, Ji-Yuan et al. (2018) Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1? Transactivation in Steatohepatitis. Cell Metab 27:1156
Alves-Paiva, Raquel M; Kajigaya, Sachiko; Feng, Xingmin et al. (2018) Telomerase enzyme deficiency promotes metabolic dysfunction in murine hepatocytes upon dietary stress. Liver Int 38:144-154
Ouyang, Xinshou; Han, Sheng-Na; Zhang, Ji-Yuan et al. (2018) Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1? Transactivation in Steatohepatitis. Cell Metab 27:339-350.e3
Gao, Bin; Xiang, Xiaogang (2018) Interleukin-22 from bench to bedside: a promising drug for epithelial repair. Cell Mol Immunol :
Li, Man; He, Yong; Zhou, Zhou et al. (2017) MicroRNA-223 ameliorates alcoholic liver injury by inhibiting the IL-6-p47phox-oxidative stress pathway in neutrophils. Gut 66:705-715
He, Yong; Gao, Bin (2017) A small specific-sized hyaluronic acid ameliorates alcoholic liver disease by targeting a small RNA: New hope for therapy? Hepatology 66:321-323

Showing the most recent 10 out of 52 publications