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

Background and Aims:

Fibroblast growth factor (FGF) 21, the major regulator of glucose and lipid homeostasis, has been shown to have a potential role in bile acid metabolism. We aim to investigate the FGF21 response in an acute-on-chronic liver injury (ACLI) model in Abcb4-/- mice with chronic hepatobiliary injury, where ethanol challenge was used as acute trigger.

Method:

Total RNA was extracted from wild-type (WT) C57BL/6J and Abcb4-/- (KO) mice, which were either fed control diet (WT/Cont and KO/Cont groups) or ethanol diet (5% v/v), followed by an acute ethanol binge (5 mg/kg) (WT/EtOH and KO/EtOH groups; n = 28/group). Hepatic expressions of Fgf21, Fgfr1, Fgfr4, Klb, Srebf1, Cyp7a1, Cyp8b1, Cyp27a1, Shp, Fxr, Ppara and Mtor as well as ileal mRNA levels of Fgf15, Fgfr1, Klb, Fxr and Diet1 were evaluated using the 2-ΔΔCt method. Plasma FGF15 and FGF21 levels were determined by ELISA. ANOVA was performed for statistics.

Results:

Fgf21 was significantly upregulated after ethanol exposure in WT and KO mice (p = 0.009 and 0.026, respectively) compared to their control diet fed counterparts. FGF21 elevation was observed in plasma of WT/EtOH and KO/EtOH groups (p = 0.040 and 0.048, respectively). Hepatic expressions of Fgfr1, Fgfr4, Klb, Srebf1, Shp, Fxr and Mtor showed no difference between groups. Cyp7a1 and Cyp27a1 were significantly repressed in livers of WT/EtOH (p = 0.044 and p = 0.007, respectively) and KO/EtOH groups (p = 0.035 and p = 0.001, respectively), compared to WT/Cont. Ethanol challenge resulted in significant induction of hepatic Ppara expression in both WT (p = 0.021) and KO mice (p = 0.023). Significant repression of Cyp8b1 was observed only in KO/EtOH group, compared to WT/Cont (p = 0.041), WT/EtOH (p = 0.029) and KO/EtOH groups (p = 0.027). While plasma FGF15 levels were not different between groups, ileal expressions of Fgf15 and Fxr were upregulated in WT/EtOH compared to WT/Cont mice (p = 0.029 and p = 0.007, respectively). Ileal Diet1 expression did not differ.

Conclusions:

Alcohol consumption markedly suppressed hepatic expression level of Cyp7a1, which encodes the rate-limiting enzyme of bile acid synthesis, regardless of the genotype. Simultaneous upregulation of Fgf21 and downregulation of Cyp7a1 in liver, together with the invariant plasma FGF15 and hepatic Shp, Fxr, Klb, Fgfr4 levels, suggest that upon ethanol challenge, bile acid metabolism may be regulated by FGF21, resulting in an inhibition of CYP7A1 through an FGF15-independent pathway in our model.