Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate-treated hepatic cells
Enhanced synthesis of saturated phospholipids is associated with ER stress and lipotoxicity in palmitate-treated hepatic cells
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DOI：
10.1194/jlr.m050237
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发表时间：
2014-07-01
影响因子：
6.5
通讯作者：
Young, Jamey D.
中科院分区：
文献类型：
--
作者：
Leamy, Alexandra K.;Egnatchik, Robert A.;Young, Jamey D.
高水平的饱和脂肪酸 (SFA) 对包括肝细胞在内的多种细胞类型具有剧毒，并且与 2 型糖尿病和非酒精性脂肪肝等疾病有关。先前已证明 SFA 积累会降低内质网 (ER) 功能，导致脂肪凋亡级联的其他表现。我们假设磷脂 (PL) 代谢功能失调是这种 ER 应激反应的起始因素。用 SFA 棕榈酸酯处理原代肝细胞或 H4IIEC3 细胞会导致 ER 膜急剧扩张，这与细胞器功能障碍的其他标志物一致。这伴随着 H4IIEC3 细胞中甘油脂从头合成的增加、二棕榈酰磷脂酸、二酰甘油和总 PL 含量的显着升高。补充油酸 (OA) 可逆转棕榈酸 (PA) 诱导的脂毒性的这些标志物。 OA/PA 共处理调节 PA 在脂质类别之间的分布，增加三酰甘油的通量，同时减少其与 PL 的结合。原代肝细胞和 H4IIEC3 肝癌细胞系中也显示出类似的趋势。总的来说，这些发现表明，改变结构 PL 的 FA 组成可以保护肝细胞免受 PA 诱导的 ER 应激和相关的脂毒性。
High levels of saturated FAs (SFAs) are acutely toxic to a variety of cell types, including hepatocytes, and have been associated with diseases such as type 2 diabetes and nonalcoholic fatty liver disease. SFA accumulation has been previously shown to degrade endoplasmic reticulum (ER) function leading to other manifestations of the lipoapoptotic cascade. We hypothesized that dysfunctional phospholipid (PL) metabolism is an initiating factor in this ER stress response. Treatment of either primary hepatocytes or H4IIEC3 cells with the SFA palmitate resulted in dramatic dilation of the ER membrane, coinciding with other markers of organelle dysfunction. This was accompanied by increased de novo glycerolipid synthesis, significant elevation of dipalmitoyl phosphatidic acid, diacylglycerol, and total PL content in H4IIEC3 cells. Supplementation with oleate (OA) reversed these markers of palmitate (PA)-induced lipotoxicity. OA/PA cotreatment modulated the distribution of PA between lipid classes, increasing the flux toward triacylglycerols while reducing its incorporation into PLs. Similar trends were demonstrated in both primary hepatocytes and the H4IIEC3 hepatoma cell line. Overall, these findings suggest that modifying the FA composition of structural PLs can protect hepatocytes from PA-induced ER stress and associated lipotoxicity.