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SUMMARY Introduction: Alcohol use disorder remains one of the major health problems worldwide, causing excess morbidity and mortality. Alcoholic liver disease constitutes one of the major components of alcohol-associated morbidity, and alcoholic cirrhosis is the leading cause of alcohol-related death. In the course of alcoholic liver disease, alterations in bile acid metabolism play a critical role, leading to impaired bile secretion and the formation of hepatotoxic mediators. Two members of the endocrine subfamily of fibroblast growth factors, FGF21 and FGF15/19, are reported to regulate bile acid biosynthesis, but only sparse data exist hitherto about their exact functions in the setting of alcohol intake and/or alcoholic liver disease. Patients and methods: Wild-type (C57BL/6J) and Abcb4 knockout mice (which develop a cholestatic liver disease mimicking primary sclerosing cholangitis) were fed with either ethanol containing or control diet (using the preestablished NIAAA - National Institute on Alcohol Abuse and Alcoholism - protocol). Tissue expression and circulating levels of FGF21 and FGF15 were measured in both groups and mouse types. Serum bile acids and mRNA expression of the major enzymes of bile acid metabolism were determined. Liver specimens were histologically examined for cholestatic damage. Furthermore, recombinant human FGF21 was added to primary murine hepatocytes in order to assess the direct effect of FGF21 on the expression of CYP7A1, which encodes the rate-limiting enzyme of hepatic bile acid synthesis. Subsequently, serum levels of FGF21 and FGF19 and oxysterols were determined in patients with alcoholic liver disease and ongoing ethanol consumption and compared to a cohort of healthy control subjects, in order to translate the experimental findings to humans. Results: Ethanol consumption consistently upregulated hepatic and circulating levels of FGF21 in both humans and rodents. The observed upregulation was preserved even in the context of preexisting cholestatic liver disease (in rodents) or alcoholic liver disease (in humans). The upregulation of FGF21 elicits in vivo and in vitro a suppression of CYP7A1. The suppression took place in a dose-dependent manner and appeared to be independent of FGF15/19 signaling. Conclusions: Ethanol intake induces increased hepatic expression and circulating levels of FGF21, which in turn represses direct bile acid biosynthesis in a dose-dependent manner. This action is retained even in the setting of preexisting liver disease and presents a potential hepatoprotective mechanism against alcohol-associated liver damage.