Susceptibility of Nrf2-null mice to steatohepatitis and cirrhosis upon consumption of a high-fat diet is associated with oxidative stress, perturbation of the unfolded protein response, and disturbance in the expression of metabolic enzymes, but not with insulin resistance

Mice lacking transcription factor NF-E2 p45-related factor 2 (Nrf2) develop more severe non-alcoholic steatohepatitis (NASH), with cirrhosis, than wild-type (Nrf2(^+/+)) mice when fed a high-fat (HF) diet for 24 weeks. Although NASH is usually associated with insulin resistance, HF-fed^{-/- Nrf2} mice exhibited better insulin sensitivity than HF-fed ^+/+Nrf2 mice. In livers of HF-fed mice, loss of Nrf2 resulted in greater induction of lipogenic genes, lower expression of ß-oxidation genes, greater reduction in AMP-activated protein kinase (AMPK) levels, and diminished acetyl-CoA carboxylase phosphorylation than in the wild-type livers, which is consistent with greater fatty acid (FA) synthesis in Nrf2^-/-livers. Moreover, primary Nrf2^-/- hepatocytes displayed lower glucose and FA oxidation than Nrf2^+/+ hepatocytes, with FA oxidation partially rescued by treatment with AMPK activators. The unfolded protein response (UPR) was perturbed in control RC-fed Nrf2^-/- livers, and this was associated with constitutive activation of NF-_kB and JNK, along with up-regulation of inflammatory genes. The HF-diet elicited an antioxidant response in Nrf2^+/+ livers, and as this was compromised in Nrf2^-/- livers they suffered oxidative stress. Therefore Nrf2 protects against NASH by suppressing lipogenesis, supporting mitochondrial function, increasing the threshold for the UPR and inflammation, and enabling adaptation to HF diet-induced oxidative stress.