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

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.

N1 - Copyright © 2014, American Society for Microbiology. All Rights Reserved.

PY - 2014/9

Y1 - 2014/9

N2 - 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.

AB - 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.

U2 - 10.1128/MCB.00677-14

DO - 10.1128/MCB.00677-14

M3 - Article

C2 - 24958099

SN - 0270-7306

VL - 34

SP - 3305

EP - 3320

JO - Molecular and Cellular Biology

JF - Molecular and Cellular Biology

IS - 17

ER -