Fibroblast Growth Factor 21 Response in a Preclinical Alcohol Model of Acute-on-Chronic Liver Injury.

BACKGROUND AND AIMS

Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. We aimed to investigate the FGF21 response in an ethanol-induced acute-on-chronic liver injury (ACLI) model in mice with deficiency of the hepatobiliary phospholipid transporter.

METHODS

Total RNA was extracted from wild-type (WT, C57BL/6J) and (KO) mice, which were either fed a control diet (WT-Cont and KO-Cont groups; = 28/group) or ethanol diet, followed by an acute ethanol binge (WT-EtOH and KO-EtOH groups; = 28/group). A total of 58 human subjects were recruited into the study, including patients with alcohol-associated liver disease (AALD; = 31) and healthy controls ( = 27). The hepatic and ileal expressions of genes involved in bile acid metabolism, plasma FGF levels, and bile acid and its precursors 7α- and 27-hydroxycholesterol (7α- and 27-OHC) concentrations were determined. Primary mouse hepatocytes were isolated for cell culture experiments.

RESULTS

Alcohol feeding significantly induced plasma FGF21 and decreased hepatic levels. Hepatic expression levels of Fibroblast growth factor receptor 1 (), , Farnesoid X-activated receptor (), and Small heterodimer partner () and plasma FGF15/FGF19 levels did not differ with alcohol challenge. Exogenous FGF21 treatment suppressed in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels while FGF19 did not differ.

CONCLUSIONS

The simultaneous upregulation of FGF21 and downregulation of expressions upon chronic plus binge alcohol feeding together with the invariant plasma FGF15 and hepatic and levels suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in this ACLI model. Lay Summary: Alcohol challenge results in the upregulation of FGF21 and repression of expressions while circulating FGF15 and hepatic and levels remain constant both in healthy and pre-injured livers, suggesting the presence of an alternative FGF15-independent regulatory mechanism of FGF21 on bile acid homeostasis through the inhibition of Cyp7a1.