ethanol develop extensive fatty liver and liver injury [52] whereas PPARα activating ligands such as clofibrate [53] or WY14643 [51] decrease the ethanol fatty liver. Levels of PPARα, and a downstream target of PPARα, AOX, were decreased more than 50% by ethanol administration to WT mice and CYP2E1 KI mice, but no effect was found with the CYP2E1 KO mice. This suggests the ethanol-induced decline in PPARα may be due, at least in part to CYP2E1, or more likely, CYP2E1-derived ROS. These results differ from Wan et al [47] who using the intragastric infusion model of ethanol administration, found that ethanol decreased PPARα levels and induced fatty liver to a greater extent in CYP2E1 KO mice than WT mice. We believe these differences may relate, in part, to differences in endotoxemia and TNFα levels in the intragastric versus oral models of ethanol administration, i.e. ROS may be produced in CYP2E1 KO mice fed ethanol intragastrically largely via TNFα generated by endotoxemia. In our oral model of ethanol administration, TNFα levels were not elevated (Fig. 1D), leading us to speculate that CYP2E1, not TNFα, is a major mechanism for ethanol-induced oxidant stress followed by steatosis.
