FGF21 is a recently-described lipid metabolism regulator (Kharitonenkov et al., 2005). Basal levels of serum FGF21 and liver FGF21 expression were elevated in Cyp2a5−/− mice compared to Cyp2a5+/+ mice. However, ethanol did not further increase serum FGF21 or liver FGF21 expression in Cyp2a5−/− mice while ethanol did elevate FGF21 in Cyp2a5+/+ mice. In liver, FGF21 is regulated by PPARα, a lipid metabolism regulator (Badman et al., 2007; Inagaki et al., 2007). Indeed, we found that serum FGF21 was almost undetectable in Pparα−/− mice and ethanol feeding did not increase serum FGF21 but ethanol did induce hypertriglyceridemia in Pparα−/− mice. In contrast, ethanol feeding induced serum FGF21 but did not cause an elevation of serum TG in Pparα+/+ mice. Administration of rFGF21 restored the blood FGF21 and normalized serum TG levels in ethanol-fed Pparα−/− mice. These results suggest that FGF21 may act as a downstream mediator of the PPARα signaling pathway, resulting in a formation of a PPARα-FGF21 axis which protecte against the development of alcoholic fatty liver. The treatment with rFGF21 led to a decrease in liver TG in Pparα+/+
