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FGF21 deficiency exacerbates chronic alcohol induced fatty liver disease via a p38MAPK and PGC‐1α mediated pathway (653.13)
Author(s) -
Liu Yanlong,
Zhao Cuiqing,
Zhang Min,
Wu Guicheng,
McClain Craig,
Feng Wenke
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.653.13
Subject(s) - fgf21 , steatosis , endocrinology , medicine , fatty liver , lipid metabolism , liver injury , alcoholic fatty liver , liver disease , beta oxidation , hepatocyte , triglyceride , biology , metabolism , cholesterol , biochemistry , fibroblast growth factor , disease , in vitro , receptor
Extrahepatic hormones, such as insulin and glucagon, are important in alcohol‐induced alteration in liver lipid metabolism. However, little is known whether the paracrine and endocrine signal for metabolic regulation of hepatic itself participates in alcohol exposure associated lipid accumulation. Fibroblast growth factor 21 (FGF21) is a hepatokine and plays a critical role in the glucose and lipid metabolism in obese and diabetic animals. Here, we demonstrated that FGF21 deficiency exacerbate chronic alcoholic liver disease (ALD). Mice were fed diet containing 5% alcohol for 4 weeks. Alcohol feeding increased hepatic fatty acid and triglyceride contents and fat accumulation in WT mice, which is exacerbated in FGF21‐KO mice. The increased hepatic steatosis was accompanied by elevated liver injury evaluated by liver enzyme levels and hepatic inflammation. Hepatocyte mitochondrial fatty acid β‐oxidation was reduced, as measured by Seahorse technology, and genes involved in the β‐oxidation were down‐regulated in FGF21‐KO mice exposed to alcohol. Further studies showed that alcohol exposure significantly decreased PGC‐1α phosphorylation and p38MAPK activation in FGF21‐KO mice. In vitro study showed that recombinant FGF21 treatment increased PGC‐1α activation, the effect was diminished by p38MAPK inhibitors. In conclusion, FGF21 is likely required for cellular capacity for fat clearance in subjects exposed to chronic alcohol through PGC‐1α activation. Grant Funding Source : Supported by NIH, DOD and Veterans Administration