Perilipin 5 Improves Hepatic Lipotoxicity by Inhibiting Lipolysis
Perilipin 5 Improves Hepatic Lipotoxicity by Inhibiting Lipolysis
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Perilipin 5 通过抑制脂肪分解来改善肝脏脂毒性。
DOI：
10.1002/hep.27409
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发表时间：
2015-03-01
期刊：
影响因子：
13.5
通讯作者：
Ye, Jing
中科院分区：
文献类型：
--
作者：
Wang, Chao;Zhao, Yuanlin;Ye, Jing
非酯化脂肪酸（NEFAs）及其衍生物的代谢异常已被报道是细胞内脂毒性损伤的主要原因。通常，NEFA以甘油三酯（TG）的形式储存在脂滴（LD）中，这可以降低胞浆NEFA的脂毒性。以往的研究表明，脂环素5（Perilipin 5，Plin 5），一种LD结合蛋白，调节LD中TG的储存和水解。然而，其在肝脏中的作用和潜在机制仍然未知。在这里，我们发现脂肪变性肝脏中Plin 5表达增加。使用Plin 5基因敲除小鼠，我们发现Plin 5缺陷导致肝脏脂质含量降低和较小的LD，这是由于脂解速率和脂肪酸利用率升高。Plin 5缺陷肝细胞表现出线粒体增殖增加，这可以通过增加NEFA水平刺激的PPAR表达和活性增加来解释。同时，Plin 5缺陷的肝脏也表现出增强的线粒体氧化能力。我们还发现Plin 5缺乏会诱导肝细胞的脂毒性损伤，归因于脂质过氧化。从机制上讲，我们发现Plin 5通过竞争性结合比较基因识别-58（CGI-58）并破坏CGI-58和ATGL之间的相互作用来阻断脂肪甘油三酯脂肪酶（ATGL）介导的脂解。结论：Plin 5是脂肪分解产生的NEFAs诱导的肝脏脂毒性的重要保护因子。这为研究肝脏脂质储存的调节以及脂质储存与脂毒性的关系提供了新的思路。（肝病学2015;61：870-882）
Abnormal metabolism of nonesterified fatty acids (NEFAs) and their derivatives has been reported to be the main cause of intracellular lipotoxic injury. Normally, NEFAs are stored in lipid droplets (LDs) in the form of triglyceride (TG), which could reduce the lipotoxicity of cytosolic NEFAs. Previous studies have implicated that Perilipin 5 (Plin5), an LD-binding protein, regulates the storage and hydrolysis of TG in LD. However, its roles and underlying mechanisms in the liver remain unknown. Here we found that Plin5 expression was increased in steatotic livers. Using Plin5 knockout mice, we found that Plin5 deficiency resulted in reduced hepatic lipid content and smaller-sized LDs, which was due to the elevated lipolysis rate and fatty acid utilization. Plin5-deficient hepatocytes showed increased mitochondria proliferation, which could be explained by the increased expression and activity of PPAR stimulated by the increased NEFA levels. Meanwhile, Plin5-deficient livers also exhibited enhanced mitochondrial oxidative capacity. We also found that Plin5 deficiency induces lipotoxic injury in hepatocytes, attributed to lipid peroxidation. Mechanistically, we found that Plin5 blocks adipose triglyceride lipase (ATGL)-mediated lipolysis by competitively binding to comparative gene identification-58 (CGI-58) and disrupting the interaction between CGI-58 and ATGL. Conclusion: Plin5 is an important protective factor against hepatic lipotoxicity induced by NEFAs generated from lipolysis. This provides an important new insight into the regulation of hepatic lipid storage and relation between lipid storage and lipotoxicity. (Hepatology 2015;61:870-882)