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Alcohol exposure increases fibroblast growth factor 21 expression

Long‐term excess alcohol exposure leads to alcohol liver disease (ALD). Alcohol‐induced hepatic fat accumulation sensitizes the liver to various “second hits” to develop more advanced liver injury. Recombinant FGF‐21 has beneficial effects in promoting adipose tissue glucose uptake, lowering circulating glucose levels, and reducing hepatic lipid content in diabetic and obese rodent and monkey models. Serum FGF‐21 is elevated in non‐alcoholic fatty liver disease, coronary heart disease and type 2 diabetes. Serum levels of FGF‐21 were significantly higher in alcoholic patients with and without liver disease. Alcohol ingestion caused a significant increase in hepatic FGF‐21 expression and elevation of serum FGF‐21 concentration in mice exposed to chronic, acute or chronic‐binge alcohol. Incubation of hepatocytes with alcohol also increased FGF‐21 mRNA expression in a dose‐dependent manner. Alcohol significantly decreases hepatic and adipose mRNA levels of FGFR4 and β‐klotho, which is a specific co‐receptor for FGF‐21. Alcohol impaired recombinant FGF‐21‐induced ERK‐1/2 phosphorylation in adipose tissue and liver in mice treated with Lieber deCarli diet containing 5% alcohol for 4 weeks. We demonstrated that alcohol exposure increases hepatic expression and serum concentration of FGF‐21, which are associated with hepatic and adipose tissue FGF‐21 resistant in ALD.