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+/+ mice but did not in Pparα−/− mice. Alcoholic fatty liver is known to be enhanced in Pparα−/− mice (Nakajima et al., 2004). In our study, liver TG accumulation was not higher in Pparα−/− mice as compared with Pparα+/+ mice, but hypertriglyceridemia was observed in the Pparα−/− mice but was not in the Pparα+/+ mice. Administration of rFGF21 blunted the elevation of serum TG in the Pparα−/− mice, indicating that FGF21 is still protective in Pparα−/− mice. Although serum TG levels were lowered by rFGF21, liver TG accumulation was not decreased by rFGF21 in Pparα−/− mice. Possible reasons for why rFGF21 did not ameliorate liver fat accumulation in Pparα−/− mice may be: 1. PPARα regulates a panel of lipid metabolism genes, and FGF21 may need to cooperate with other PPARα-regulated genes to exert hepatic lowering effects; 2. While the rFGF21 dose (0.25mg/kg) was sufficient to exert actions in the Pparα+/+ mice (where endogenous FGF21 is also produced), it may not be
