Shiozaki Yuji, Miyazaki-Anzai Shinobu, Okamura Kayo, Keenan Audrey L, Masuda Masashi, Miyazaki Makoto
Division of Renal Diseases and Hypertension, University of Colorado-Denver, Aurora, CO, USA.
Division of Renal Diseases and Hypertension, University of Colorado-Denver, Aurora, CO, USA.
iScience. 2020 May 22;23(5):101105. doi: 10.1016/j.isci.2020.101105. Epub 2020 Apr 27.
Excessive 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.
过量的饱和脂肪酸对血管平滑肌细胞（VSMC）具有毒性。我们之前报道过，缺乏血管平滑肌细胞硬脂酰辅酶A去饱和酶（SCD）的小鼠会出现严重的血管钙化，SCD是催化饱和脂肪酸解毒的一种主要酶，缺乏该酶会导致含有饱和脂肪酸的脂质代谢产物大量积累。然而，SCD缺乏导致血管钙化的机制尚未完全明确。在此，我们证明饱和脂肪酸会显著抑制血管平滑肌细胞中的自噬流，从而导致血管钙化和细胞凋亡。从机制上来说，饱和脂肪酸以饱和溶血磷脂酸（LPA）（即1-硬脂酰-LPA）的形式积累，可能是通过甘油-3-磷酸酰基转移酶4（GPAT4）在ω小体与线粒体相关内质网膜（MAM）的接触位点发生反应而合成的。饱和LPA在接触位点的积累会导致ω小体异常形成，从而导致自噬体前体隔离膜的积累，进而抑制自噬流。因此，饱和LPA是介导自噬抑制和血管钙化的主要代谢产物。
