Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells.
Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells.
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DOI：
10.1194/jlr.m043299
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发表时间：
2014-01
影响因子：
6.5
通讯作者：
Stangl H
中科院分区：
文献类型：
--
作者：
Röhrl C;Eigner K;Winter K;Korbelius M;Obrowsky S;Kratky D;Kovacs WJ;Stangl H
代谢紊乱如2型糖尿病引起肝内质网（ER）应激，其影响中性脂质代谢。然而，ER应激在胆固醇代谢中的作用还不完全清楚。在这里，我们表明，诱导急性ER应激在人肝HepG 2细胞减少ABCA 1的表达，并导致ABCA 1重新分配到管状核周区室。因此，胆固醇流出apoA-I，新生HDL形成的关键步骤，减少了80%。除了ABCA 1，内源性apoA-I表达减少ER应激诱导，这有助于减少胆固醇流出。肝脏X受体是外周细胞中ABCA 1的关键调节因子，但不参与这一过程。尽管减少胆固醇流出，细胞胆固醇水平保持不变，在ER应激。这是由于HMG-CoA还原酶活性降低70%，导致胆固醇从头合成受损，尽管诱导了固醇反应元件结合蛋白-2活性。在小鼠中，ER应激诱导导致肝脏ABCA 1表达显著减少。然而，高密度脂蛋白胆固醇水平没有改变，可能是因为清道夫受体B类，I型下调下ER压力。综上所述，我们的数据表明，ER应激在代谢紊乱减少HDL生物合成由于受损的肝脏ABCA 1功能。
Metabolic disorders such as type 2 diabetes cause hepatic endoplasmic reticulum (ER) stress, which affects neutral lipid metabolism. However, the role of ER stress in cholesterol metabolism is incompletely understood. Here, we show that induction of acute ER stress in human hepatic HepG2 cells reduced ABCA1 expression and caused ABCA1 redistribution to tubular perinuclear compartments. Consequently, cholesterol efflux to apoA-I, a key step in nascent HDL formation, was diminished by 80%. Besides ABCA1, endogenous apoA-I expression was reduced upon ER stress induction, which contributed to reduced cholesterol efflux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol efflux, cellular cholesterol levels remained unchanged during ER stress. This was due to impaired de novo cholesterol synthesis by reduction of HMG-CoA reductase activity by 70%, although sterol response element-binding protein-2 activity was induced. In mice, ER stress induction led to a marked reduction of hepatic ABCA1 expression. However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress. Taken together, our data suggest that ER stress in metabolic disorders reduces HDL biogenesis due to impaired hepatic ABCA1 function.