The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis
The Lipid Droplet Protein Hypoxia-inducible Gene 2 Promotes Hepatic Triglyceride Deposition by Inhibiting Lipolysis
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DOI：
10.1074/jbc.m115.650184
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发表时间：
2015-06-12
影响因子：
4.8
通讯作者：
Czech, Michael P.
中科院分区：
文献类型：
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作者：
DiStefano, Marina T.;Danai, Laura V.;Czech, Michael P.
肝脏是葡萄糖、脂肪酸和甘油三酯 (TG) 合成的主要场所，是全身营养稳态的主要调节器。人类或啮齿动物长期接触高热量饮食会促进非酒精性脂肪肝疾病，其特征是肝细胞脂滴（LD）中中性脂质积累。在这里，我们发现LD蛋白缺氧诱导基因2（Hig2/Hilpda）通过减弱TG水解来增强肝细胞中的脂质积累。高脂饮食和禁食期间小鼠肝脏中 Hig2 表达增加，这两种状态与肝脏 TG 含量增加相关。 Hig2 在原代小鼠肝细胞中表达，定位于 LD，并在油酸存在的情况下促进 LD TG 沉积。相反，他莫昔芬诱导的 Hig2 缺失降低了含有 floxed 等位基因 Hig2 和由泛素 C 启动子控制的 cre/ERT2 转基因的小鼠原代肝细胞中的 TG 含量和 LD 大小。在具有受白蛋白启动子控制的 floxed Hig2 表达 cre 的小鼠中，肝脏特异性删除 Hig2 也降低了肝脏 TG。重要的是，我们证明与对照相比，Hig2 缺陷的肝细胞表现出 TG 脂解、TG 周转和脂肪酸氧化增加。有趣的是，肝脏特异性 Hig2 缺失的小鼠也表现出葡萄糖耐量的改善。总而言之，这些数据表明 Hig2 通过损害 TG 降解的机制，在促进小鼠肝细胞 LD 内的脂质隔离方面发挥着重要作用。
The liver is a major site of glucose, fatty acid, and triglyceride (TG) synthesis and serves as a major regulator of whole body nutrient homeostasis. Chronic exposure of humans or rodents to high-calorie diets promotes non-alcoholic fatty liver disease, characterized by neutral lipid accumulation in lipid droplets (LD) of hepatocytes. Here we show that the LD protein hypoxia-inducible gene 2 (Hig2/Hilpda) functions to enhance lipid accumulation in hepatocytes by attenuating TG hydrolysis. Hig2 expression increased in livers of mice on a high-fat diet and during fasting, two states associated with enhanced hepatic TG content. Hig2 expressed in primary mouse hepatocytes localized to LDs and promoted LD TG deposition in the presence of oleate. Conversely, tamoxifen-inducible Hig2 deletion reduced both TG content and LD size in primary hepatocytes from mice harboring floxed alleles of Hig2 and a cre/ERT2 transgene controlled by the ubiquitin C promoter. Hepatic TG was also decreased by liver-specific deletion of Hig2 in mice with floxed Hig2 expressing cre controlled by the albumin promoter. Importantly, we demonstrate that Hig2-deficient hepatocytes exhibit increased TG lipolysis, TG turnover, and fatty acid oxidation as compared with controls. Interestingly, mice with liver-specific Hig2 deletion also display improved glucose tolerance. Taken together, these data indicate that Hig2 plays a major role in promoting lipid sequestration within LDs in mouse hepatocytes through a mechanism that impairs TG degradation.