Acute accumulation of free cholesterol induces the degradation of perilipin 2 and Rab18-dependent fusion of ER and lipid droplets in cultured human hepatocytes.
Acute accumulation of free cholesterol induces the degradation of perilipin 2 and Rab18-dependent fusion of ER and lipid droplets in cultured human hepatocytes.
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DOI：
10.1091/mbc.e15-10-0730
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发表时间：
2016-11-01
影响因子：
3.3
通讯作者：
Kobayashi T
中科院分区：
文献类型：
--
作者：
Makino A;Hullin-Matsuda F;Murate M;Abe M;Tomishige N;Fukuda M;Yamashita S;Fujimoto T;Vidal H;Lagarde M;Delton I;Kobayashi T
肝脏中游离胆固醇的蓄积与非酒精性脂肪性肝炎的发病机制有关。急性游离胆固醇蓄积诱导LDs融合，随后LDs的外壳蛋白、围脂蛋白2降解，载脂蛋白100以Rab 18依赖的方式与LDs结合。肝脏胆固醇稳态失调伴肝脏中游离胆固醇蓄积与非酒精性脂肪性肝炎的发病机制相关，导致肝毒性的慢性化。在这里，我们研究了游离胆固醇积累对培养肝细胞中脂滴（LDs）的形态和生化特性的影响。急性游离胆固醇蓄积诱导LD融合，随后是LD的外壳蛋白周脂蛋白2（PLIN 2;也称为亲脂蛋白或脂肪分化相关蛋白）降解，以及载脂蛋白B 100（Apo B 100）与LD的结合。PLIN 2的降解被泛素化、自噬和蛋白质合成的抑制剂抑制。结果表明，ApoB 100与LD的关联依赖于低分子量GTP结合蛋白Rab 18的活性，并突出了LD作为肝细胞中游离胆固醇毒性靶点的作用。
Free cholesterol accumulation in the liver is relevant to the pathogenesis of nonalcoholic steatohepatitis. Acute free cholesterol accumulation induced the fusion of LDs, followed by degradation of the coat protein of LDs, perilipin 2, and association of apolipoprotein 100 to LDs in Rab18-dependent manner. Dysregulated hepatic cholesterol homeostasis with free cholesterol accumulation in the liver is relevant to the pathogenesis of nonalcoholic steatohepatitis, contributing to the chronicity of liver toxicity. Here we examined the effect of free cholesterol accumulation on the morphology and biochemical properties of lipid droplets (LDs) in cultured hepatocytes. Acute free cholesterol accumulation induced the fusion of LDs, followed by degradation of the coat protein of LDs, perilipin 2 (PLIN2; also called adipophilin or adipose differentiation–related protein), and association of apolipoprotein B 100 (ApoB 100) to LDs. The degradation of PLIN2 was inhibited by inhibitors of ubiquitination, autophagy, and protein synthesis. The results indicate that association of ApoB 100 with LDs is dependent on the activity of low–molecular weight GTP-binding protein Rab18 and highlight the role of LDs as targets of free cholesterol toxicity in hepatocytes.