論文

査読有り 国際誌
2020年4月27日

GPAT4-Generated Saturated LPAs Induce Lipotoxicity through Inhibition of Autophagy by Abnormal Formation of Omegasomes.

iScience
  • Yuji Shiozaki
  • ,
  • Shinobu Miyazaki-Anzai
  • ,
  • Kayo Okamura
  • ,
  • Audrey L Keenan
  • ,
  • Masashi Masuda
  • ,
  • Makoto Miyazaki

23
5
開始ページ
101105
終了ページ
101105
記述言語
英語
掲載種別
DOI
10.1016/j.isci.2020.101105

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.

リンク情報
DOI
https://doi.org/10.1016/j.isci.2020.101105
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/32408172
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225743