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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.