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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.
Mol Cell Biol. 2014 Sep; 34(17):3305-20.MC

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+Show Affiliations

Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Department of Pathology, Ninewells Hospital and Medical School, Tayside NHS Trust, Dundee, Scotland, United Kingdom.Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Division of Cancer Research, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.Medical Research Institute, Division of Cardiovascular and Diabetes Medicine, Ninewells Hospital and Medical School, University of Dundee, Dundee, Scotland, United Kingdom.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.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.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

24958099

Citation

Meakin, Paul J., et al. "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." Molecular and Cellular Biology, vol. 34, no. 17, 2014, pp. 3305-20.
Meakin PJ, Chowdhry S, Sharma RS, et al. 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. Mol Cell Biol. 2014;34(17):3305-20.
Meakin, P. J., Chowdhry, S., Sharma, R. S., Ashford, F. B., Walsh, S. V., McCrimmon, R. J., Dinkova-Kostova, A. T., Dillon, J. F., Hayes, J. D., & Ashford, M. L. (2014). 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. Molecular and Cellular Biology, 34(17), 3305-20. https://doi.org/10.1128/MCB.00677-14
Meakin PJ, et al. 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. Mol Cell Biol. 2014;34(17):3305-20. PubMed PMID: 24958099.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Meakin,Paul J, AU - Chowdhry,Sudhir, AU - Sharma,Ritu S, AU - Ashford,Fiona B, AU - Walsh,Shaun V, AU - McCrimmon,Rory J, AU - Dinkova-Kostova,Albena T, AU - Dillon,John F, AU - Hayes,John D, AU - Ashford,Michael L J, Y1 - 2014/06/23/ PY - 2014/6/25/entrez PY - 2014/6/25/pubmed PY - 2015/2/14/medline SP - 3305 EP - 20 JF - Molecular and cellular biology JO - Mol Cell Biol VL - 34 IS - 17 N2 - 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. SN - 1098-5549 UR - https://www.unboundmedicine.com/medline/citation/24958099/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_ L2 - http://mcb.asm.org/lookup/pmidlookup?view=long&pmid=24958099 DB - PRIME DP - Unbound Medicine ER -