Obesity, NAFLD, NASH, and HFD were reported to contribute to high incidence of IR which may worsen the NASH condition, mainly due to increased levels of oxidative/nitrative stress and inflammation [1,7,39]. Furthermore, it was shown that overexpression of hepatic CYP2E1 both in vitro and in vivo promotes the development of hepatic IR partly through activation (phosphorylation) of JNK [12,40]. Thus we also evaluated whether CYP2E1 deletion would lead to the development of IR and impaired GT. Our data revealed that only WT-HFD, but not the other groups developed IR and impaired GT (Fig. 4), which supports the notion that increased CYP2E1 in HFD for an extended period likely promotes IR and that the absence or blocking of CYP2E1 may exert beneficial effects. During the final preparation of this manuscript, a detailed report showed the role CYP2E1 deletion in the development of IR in the same mice strain, same diet and very similar duration of feeding [41]. Pessin and colleagues demonstrated that, using euglycemic-hyperinsulinemic clamps, the Cyp2e1-null mice were protected substantially against HFD-induced hepatic IR and exhibited better sensitivity of adipose
