Previously, we reported that ethanol induction of CYP2A5 was regulated by a NRF2-dependent pathway (Lu et al., 2012). Here, we found that CYP2A5 induction by ethanol was blunted in Nrf2−/− mice while CYP2E1 induction was not affected (Fig 3A, B). Basal FGF21 expression was undetectable in Nrf2−/− mice, which is consistent with the report that Nrf2 regulates FGF21 (Furusawa et al., 2014). However, ethanol was capable of inducing FGF21 in Nrf2−/− mice, although the FGF21 induction by ethanol was weaker compared with Nrf2+/+ mice (Fig 3A, B). Interestingly, basal expression of PPARα, a major regulator of FGF21 in liver, was upregulated in Nrf2−/− mice (Fig 3A, B). To explore the vital role of PPARα in ethanol induction of FGF21, Pparα−/− mice and Pparα+/+ mice were fed ethanol. As shown in Fig 4A, serum FGF21 was almost undetectable in Pparα−/− mice, which is consistent with the notion that FGF21 is regulated by PPARα (Badman et al., 2007; Inagaki et al., 2007). After ethanol feeding, while serum FGF21 was increased in Pparα+/+ mice, serum FGF21 was still undetectable in Pparα−/− mice. Administration
