Both mouse CYP2A5 and human CYP2A6 are regulated by NRF2 (Lu et al., 2012; Yokota et al., 2011). Recently, we found that ethanol induction of CYP2A5 was lower in Nrf2−/− mice than in Nrf2+/+ mice, suggesting that ethanol induction of CYP2A5 was also regulated, at least in part, by NRF2-dependent pathway (Lu et al., 2012). Redox sensitive NRF2 usually up-regulates a panel of antioxidant enzymes to antagonize oxidative stress (Cederbaum, 2009) and NRF2 deficiency enhanced alcoholic liver injury in mice (Lamlé et al., 2008), suggesting that NRF2 protects against alcoholic liver injury via its antioxidant promoting effects. Whether Cyp2a5 is among the panel of NRF2-regulated antioxidant genes is still unclear, but CYP2A5 may act as an antioxidant to protect against alcohol-induced oxidative liver injury (Hong et al., 2015). NRF2 can also regulate FGF21 expression (Furusawa et al., 2014). Does NRF2 also exert effects via FGF21? Here we found that ethanol induction of FGF21 was also lower in Nrf2−/− mice, which is consistent with the more severe alcoholic liver injury in Nrf2−/− mice (Lamlé et al., 2008). Thus, in addition to its antioxidant promoting effects, NRF2 may also regulate hepatic lipid metabolism through FGF21.
