Fibroblast growth factor 21 response in a preclinical alcohol model of acute-on-chronic liver injury

Background Fibroblast growth factor (FGF) 21 has recently been shown to play a potential role in bile acid metabolism. Our aim was to investigate the FGF21 response in the ethanol-induced acute-on-chronic liver injury (ACLI) model in Abcb4-/- (KO) mice with deficiency of the hepatobiliary phosphatidylcholine transporter.

Patients and methods Total RNA was extracted from Abcb4-/- mice and wild-type (WT, C57BL/6J) controls, which were either fed control diet (WT/Cont and KO/Cont groups; n= 22/group) or ethanol diet, followed by an acute ethanol binge (WT/EtOH and KO/EtOH groups; n= 22/group). A total of 58 human subjects were recruited into the study including alcohol-associated liver disease patients (AALD; n = 31) and healthy controls (n = 27). Hepatic and ileal expression of genes involved in bile acid mechanism, plasma FGF concentrations (ELISA) and bile acid levels were analyzed. Serum concentrations of human oxysterols 7α and 27-hydroxycholesterol were quantified by isotope dilution GC-mass spectrometry selected ion-monitoring (GC-MS-SIM). Primary mouse hepatocytes were used for cell culture experiments.

Result Alcohol feeding significantly induced FGF21 and decreased hepatic Cyp7a1 levels. Hepatic steady-state mRNA levels of Fxr, Shp, Fgfr1 and Fgfr4, and plasma FGF15/FGF19 levels did not differ with or without alcohol challenge. Recombinant human FGF21 (rhFGF21) suppressed Cyp7a1 in a dose-dependent manner in vitro. AALD patients showed markedly higher FGF21 and lower 7α-OHC plasma levels in the setting of constant FGF19 concentrations.

Conclusions Simultaneous upregulation of FGF21 and repression of Cyp7a1 expression upon chronic plus binge alcohol feeding together with invariant plasma FGF15 and hepatic Shp and Fxr expression suggest the presence of a direct regulatory mechanism of FGF21 on bile acid homeostasis through inhibition of CYP7A1 by an FGF15-independent pathway in the ACLI model. In accordance with the in vivo results, our translational human studies demonstrate significant FGF21 upregulation and significant reduction of serum 7αOHC levels in AALD patients upon ongoing ethanol consumption with unchanged plasma FGF19 levels. The in vitro studies indicate a direct effect of FGF21 on hepatic Cyp7a1 mRNA suppression in a dose-dependent manner.

Publication History

Article published online:
04 January 2021