GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice
GCN2 deficiency protects against high fat diet induced hepatic steatosis and insulin resistance in mice
复制标题
GCN2 缺乏可预防高脂肪饮食引起的小鼠肝脂肪变性和胰岛素抵抗。
DOI：
10.1016/j.bbadis.2018.07.012
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发表时间：
2018-10-01
影响因子：
6.2
通讯作者：
Lu, Zhongbing
中科院分区：
文献类型：
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作者：
Liu, Shasha;Yuan, Juntao;Lu, Zhongbing
非酒精性脂肪性肝病（NAFLD）以肝脏脂质沉积和氧化应激为特征。研究表明，在氨基酸剥夺的条件下，一般控制非抑制2 （GCN2）是维持肝脏脂肪酸稳态所必需的。然而，GCN2对NAFLD发展的影响尚未被研究。在这项研究中，我们使用Gcn2（-/-）小鼠来研究Gcn2对高脂肪饮食（HFD）诱导的肝脂肪变性的影响。饲喂HFD 12周后，Gcn2（-/-）小鼠的肥胖程度低于野生型（WT）小鼠，Gcn2（-/-）显著减轻HFD诱导的肝功能障碍、肝脂肪变性和胰岛素抵抗。在饲喂hfd的小鼠肝脏中，GCN2缺乏导致脂肪分解基因水平升高，与FA合成、运输和脂肪生成相关的基因表达降低，氧化应激诱导减少。此外，我们发现GCN2的敲除减弱，而GCN2的过表达加剧了棕榈酸诱导的HepG2细胞脂肪变性、氧化和内质网应激以及过氧化物酶体增殖体激活受体γ (PPAR γ)、脂肪酸合成酶（FAS）和金属硫蛋白（MT）表达的变化。总的来说，我们的数据提供了证据，证明GCN2缺乏通过抑制脂肪生成和减少氧化应激来防止hfd诱导的肝脏脂肪变性。我们的研究结果表明，抑制肝脏中GCN2活性的策略可能为减轻NAFLD的发展提供了一种新的途径。
Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic lipid deposition and oxidative stress. It has been demonstrated that general control nonderepressible 2 (GCN2) is required to maintain hepatic fatty acid homeostasis under conditions of amino acid deprivation. However, the impact of GCN2 on the development of NAFLD has not been investigated. In this study, we used Gcn2(-/-) mice to investigate the effect of GCN2 on high fat diet (HFD)-induced hepatic steatosis. After HFD feeding for 12 weeks, Gcn2(-/-) mice were less obese than wild-type (WT) mice, and Gcn2(-/-) significantly attenuated HFD-induced liver dysfunction, hepatic steatosis and insulin resistance. In the livers of the HFD-fed mice, GCN2 deficiency resulted in higher levels of lipolysis genes, lower expression of genes related to FA synthesis, transport and lipogenesis, and less induction of oxidative stress. Furthermore, we found that knockdown of GCN2 attenuated, whereas overexpression of GCN2 exacerbated, palmitic acid -induced steatosis, oxidative & ER stress, and changes of peroxisome proliferator-activated receptor gamma (PPAR gamma), fatty acid synthase (FAS) and metallothionein (MT) expression in HepG2 cells. Collectively, our data provide evidences that GCN2 deficiency protects against HFD-induced hepatic steatosis by inhibiting lipogenesis and reducing oxidative stress. Our findings suggest that strategies to inhibit GCN2 activity in the liver may provide a novel approach to attenuate NAFLD development.