文章基本信息

标题：GPAT4-Generated Saturated LPAs Induce Lipotoxicity through Inhibition of Autophagy by Abnormal Formation of Omegasomes
本地全文：下载
作者：Yuji Shiozaki ; Shinobu Miyazaki–Anzai ; Kayo Okamura 等
期刊名称：iScience
印刷版ISSN：2589-0042
出版年度：2020
卷号：23
期号：5
页码：1-52
DOI：10.1016/j.isci.2020.101105
语种：English
出版社：Elsevier
摘要：SummaryExcessive levels of saturated fatty acids are toxic to vascular smooth muscle cells (VSMCs). We previously reported that mice lacking VSMC-stearoyl-CoA desaturase (SCD), a major enzyme catalyzing the detoxification of saturated fatty acids, develop severe vascular calcification from the massive accumulation of lipid metabolites containing saturated fatty acids. However, the mechanism by which SCD deficiency causes vascular calcification is not completely understood. Here, we demonstrate that saturated fatty acids significantly inhibit autophagic flux in VSMCs, contributing to vascular calcification and apoptosis. Mechanistically, saturated fatty acids are accumulated as saturated lysophosphatidic acids (LPAs) (i.e. 1-stearoyl-LPA) possibly synthesized through the reaction of GPAT4 at the contact site between omegasomes and the MAM. The accumulation of saturated LPAs at the contact site causes abnormal formation of omegasomes, resulting in accumulation of autophagosomal precursor isolation membranes, leading to inhibition of autophagic flux. Thus, saturated LPAs are major metabolites mediating autophagy inhibition and vascular calcification.Graphical AbstractDisplay OmittedHighlights•SMC-specific autophagy deficiency aggravates vascular calcification in CKD•SFAs block autophagy by accumulating saturated LPAs in MAM via GPAT4•SFA-LPAs induce abnormal omegasome formation and isolation membrane accumulation•UFA-LPAs attenuate SFA-induced abnormal omegasome formation and vascular calcificationMolecular Biology; Cell Biology; Lipidomics