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

• Published in: Molecular and cellular biology Vol. 34; no. 17; pp. 3305 - 3320
• Main Authors: Meakin, Paul J., Chowdhry, Sudhir, Sharma, Ritu S., Ashford, Fiona B., Walsh, Shaun V., McCrimmon, Rory J., Dinkova-Kostova, Albena T., Dillon, John F., Hayes, John D., Ashford, Michael L. J.
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 01.09.2014; American Society for Microbiology
• Subjects: acetyl coenzyme A; Acetyl-CoA Carboxylase - metabolism; AMP-activated protein kinase; AMP-Activated Protein Kinases - metabolism; Animals; antioxidant activity; Diet, High-Fat - adverse effects; Disease Susceptibility; Endoplasmic Reticulum Stress; fatty acids; fatty liver; glucose; hepatocytes; high fat diet; inflammation; Insulin Resistance; Lipid Metabolism - genetics; lipogenesis; Lipogenesis - genetics; Liver - metabolism; Liver - pathology; Liver Cirrhosis, Experimental - etiology; Liver Cirrhosis, Experimental - genetics; Liver Cirrhosis, Experimental - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; mitochondria; NF-E2-Related Factor 2 - deficiency; NF-E2-Related Factor 2 - genetics; NF-E2-Related Factor 2 - metabolism; Non-alcoholic Fatty Liver Disease - etiology; Non-alcoholic Fatty Liver Disease - genetics; Non-alcoholic Fatty Liver Disease - metabolism; oxidation; Oxidative Stress; Phosphorylation; Signal Transduction; transcription factors; Unfolded Protein Response
• ISSN: 1098-5549; 0270-7306; 1098-5549
• DOI: 10.1128/MCB.00677-14

Mice lacking the transcription factor NF-E2 p45-related factor 2 (Nrf2) develop more severe nonalcoholic 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 β-oxidation genes, greater reduction in AMP-activated protein kinase (AMPK) levels, and diminished acetyl coenzyme A (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 regular-chow (RC)-fed Nrf2 −/− mouse livers, and this was associated with constitutive activation of NF-κB and JNK, along with upregulation 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.