title: 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.
abstract: 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.
authors: Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Paul J
authors: PJ
authors: Meakin
authors: Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Sudhir
authors: S
authors: Chowdhry
authors: Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Ritu S
authors: RS
authors: Sharma
authors: Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Fiona B
authors: FB
authors: Ashford
authors: Department of Pathology, Ninewells Hospital and Medical School, Tayside NHS Trust, Dundee, Scotland, United Kingdom.
authors: Shaun V
authors: SV
authors: Walsh
authors: Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Rory J
authors: RJ
authors: McCrimmon
authors: Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: Albena T
authors: AT
authors: Dinkova-Kostova
authors: Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.
authors: John F
authors: JF
authors: Dillon
authors: Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom m.l.j.ashford@dundee.ac.uk j.d.hayes@dundee.ac.uk.
authors: John D
authors: JD
authors: Hayes
authors: Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom m.l.j.ashford@dundee.ac.uk j.d.hayes@dundee.ac.uk.
authors: Michael L J
authors: ML
authors: Ashford
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004198:Disease Susceptibility; D059865:Endoplasmic Reticulum Stress; D007333:Insulin Resistance; D050356:Lipid Metabolism / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008106:Liver Cirrhosis, Experimental / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051267:NF-E2-Related Factor 2 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D018384:Oxidative Stress; D010766:Phosphorylation; D015398:Signal Transduction; D056811:Unfolded Protein Response
chemical_list: D051267:NF-E2-Related Factor 2; C495636:Nfe2l2 protein, mouse; D055372:AMP-Activated Protein Kinases; D000103:Acetyl-CoA Carboxylase