Background and aims:
The fibroblast growth factor (FGF) 21, which is known to be a stress-induced hormone
in liver, has recently been shown to have a regulatory role in bile acid metabolism.
In this study, we aim to investigate FGF21 response in acute on chronic liver injury
(ACLI) model in Abcb4
-/- mice using ethanol challenge as the acute trigger.
Method:
Total RNA was extracted from liver tissue of 15 week-old wild type (WT) C57BL/6J and
Abcb4 knock-out (KO) mice which were either fed with control diet (WT/Cont and KO/Cont
groups) or liquid ethanol diet (5% v/v) followed by an acute ethanol binge (5 mg/kg)
(WT/EtOH and KO/EtOH groups). Each group consisted of 16 mice (n = 64). Hepatic mRNA
levels of Fgf21, Fgf15, Fgfr1, Fgfr4, Klb, Srebf1, Cyp7a1, Fxr, Shp, mTOR and Ppar-α were evaluated using 2-ΔΔCt method. Gapdh was used as an internal control. ELISA was performed for FGF15 and FGF21 using plasma
samples. ANOVA followed by Bonferroni posthoc test was performed. P < 0.05 was considered
as significant.
Results:
FGF21 response was significantly upregulated in WT/EtOH (p = 0.048) and KO/EtOH (p
= 0.043) mice compared to their control diet fed counterparts, although no significant
difference was found between genotypes. Elevation of FGF21 was also observed in plasma
samples of WT/EtOH (p = 0.040) and KO/EtOH (p = 0.048) mice with similar statistical
significance. Fgf15 expression was not observed in mice. FGF15 plasma levels showed no difference between
groups. Expressions of Klb (p = 0.049) and Shp (p = 0.047) were significantly downregulated in KO/EtOH mice compared to the WT/Cont
mice. Any significant difference was not observed for Srebf1, Fgfr1, Fgfr4, Fxr and mTOR expression levels between groups. Ethanol challenge resulted in about 2-fold increase
in Ppar-α expression in both WT (p = 0.021) and Abcb4
-/- mice (p = 0.028). Expression level of Cyp7a1 was significantly downregulated in WT/EtOH (p = 0.009) and KO/EtOH (p = 0.008) mice
when compared to WT controls.
Conclusion:
Upon ethanol challenge, bile acid metabolism might be regulated by upregulation of
FGF21 resulting in an inhibition of CYP7A1 through a metabolic pathway independent
of FGF15. Moreover, alcohol consumption might result in a Ppar-α dependent but mTOR
independent regulation of FGF21 in this ACLI model.
