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.
Highlights
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
The results presented here show that knockout of Nrf2 renders mice more sensitive to NASH when placed on an HF diet
Our data indicate that the increase in steatosis in Nrf2Ϫ/Ϫ mice placed on the HF diet is due to a heightened level of induction of lipogenesis genes and suppression of -oxidation genes compared with wild-type animals
Summary
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. 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-B and JNK, along with upregulation of inflammatory genes. Nonalcoholic fatty liver disease (NAFLD) is a common condition that is associated with obesity, type 2 diabetes mellitus, and insulin resistance [1, 2] It represents a spectrum of phenotypes ranging from simple steatosis (fatty infiltration) through nonalcoholic steatohepatitis (NASH) to fibrosis and cirrhosis. Oxidative stress activates nuclear factor B (NF-B) and c-Jun N-terminal kinase (JNK), leading to induction of inflammatory genes, which in turn increase neutrophil recruitment to the liver and exacerbate both oxidative stress and inflammation [14]. The ability of Keap to direct Nrf for proteasomal degradation is blocked by thiol-reactive agents, September 2014 Volume 34 Number 17
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