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.
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.
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DOI：
10.1128/mcb.00677-14
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发表时间：
2014-09
影响因子：
5.3
通讯作者：
Ashford ML
中科院分区：
文献类型：
--
作者：
Meakin PJ;Chowdhry S;Sharma RS;Ashford FB;Walsh SV;McCrimmon RJ;Dinkova-Kostova AT;Dillon JF;Hayes JD;Ashford ML
当喂食高脂肪 (HF) 饮食 24 周时，缺乏转录因子 NF-E2 p45 相关因子 2 (Nrf2) 的小鼠比野生型 (Nrf2+/+) 小鼠会出现更严重的非酒精性脂肪性肝炎 (NASH) 并伴有肝硬化。尽管 NASH 通常与胰岛素抵抗相关，但高频喂养的 Nrf2−/− 小鼠比高频喂养的 Nrf2+/+ 小鼠表现出更好的胰岛素敏感性。在HF喂养小鼠的肝脏中，与野生型肝脏相比，Nrf2的缺失导致脂肪生成基因的诱导更大、β-氧化基因的表达降低、AMP激活蛋白激酶（AMPK）水平的更大降低以及乙酰辅酶A（CoA）羧化酶磷酸化的减少，这与Nrf2−/−肝脏中脂肪酸（FA）合成更多是一致的。此外，原代Nrf2−/−肝细胞表现出比Nrf2+/+肝细胞更低的葡萄糖和FA氧化，其中FA氧化通过AMPK激活剂处理得到部分挽救。在对照常规饲料 (RC) 喂养的 Nrf2−/− 小鼠肝脏中，未折叠蛋白反应 (UPR) 受到干扰，这与 NF-κB 和 JNK 的组成型激活以及炎症基因的上调有关。 HF 饮食在 Nrf2+/+ 肝脏中引发抗氧化反应，并且由于 Nrf2−/− 肝脏中的抗氧化反应受到损害，因此它们遭受了氧化应激。因此，Nrf2 通过抑制脂肪生成、支持线粒体功能、提高 UPR 和炎症阈值以及适应 HF 饮食诱导的氧化应激来预防 NASH。
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.