ER stress inhibition enhances formation of triacylglcerols and protects endothelial cells from lipotoxicity

Igor Kovacevic*, Paula Henriette Schmidt, Annkatrin Kowalski, Bernd J Helms, Chris H A van de Lest, Alexander Kluttig, Guido Posern

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Elevated concentrations of palmitate in serum of obese individuals can impair endothelial function, contributing to development of cardiovascular disease. Although several molecular mechanisms of palmitate-induced endothelial dysfunction have been proposed, there is no consensus on what signaling event is the initial trigger of detrimental palmitate effects. Here we report that inhibitors of ER stress or ceramid synthesis can rescue palmitate-induced autophagy impairment in macro- and microvascular endothelial cells. Furthermore, palmitate-induced cholesterol synthesis was reverted using these inhibitors. Similar to cell culture data, autophagy markers were increased in serum of obese individuals. Subsequent lipidomic analysis revealed that palmitate changed the composition of membrane phospholipids in endothelial cells and that these effects were not reverted upon application of above-mentioned inhibitors. However, ER stress inhibition in palmitate-treated cells enhanced the synthesis of trilglycerides and restored ceramide levels to control condition. Our results suggest that palmitate induces ER-stress presumably by shift in membrane architecture, leading to impaired synthesis of triglycerides and enhanced production of ceramides and cholesterol, which altogether enhances lipotoxicity of palmitate in endothelial cells.

Original languageEnglish
Article number304
Pages (from-to)1-21
Number of pages21
JournalCell Communication and Signaling
Volume22
Issue number1
DOIs
Publication statusPublished - 3 Jun 2024

Keywords

  • Autophagy/drug effects
  • Ceramides/metabolism
  • Cholesterol/metabolism
  • Endoplasmic Reticulum Stress/drug effects
  • Endothelial Cells/drug effects
  • Humans
  • Palmitates/pharmacology
  • Triglycerides/metabolism

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