Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)
7 Downloads (Pure)

Abstract

A key event in atherogenesis is the formation of lipid-loaded macrophages, lipidotic cells, which exhibit irreversible accumulation of undigested modified low-density lipoproteins (LDL) in lysosomes. This event culminates in the loss of cell homeostasis, inflammation, and cell death. Nevertheless, the exact chemical etiology of atherogenesis and the molecular and cellular mechanisms responsible for the impairment of lysosome function in plaque macrophages are still unknown. Here, we demonstrate that macrophages exposed to cholesteryl hemiazelate (ChA), one of the most prevalent products of LDL-derived cholesteryl ester oxidation, exhibit enlarged peripheral dysfunctional lysosomes full of undigested ChA and neutral lipids. Both lysosome area and accumulation of neutral lipids are partially irreversible. Interestingly, the dysfunctional peripheral lysosomes are more prone to fuse with the plasma membrane, secreting their undigested luminal content into the extracellular milieu with potential consequences for the pathology. We further demonstrate that this phenotype is mechanistically linked to the nuclear translocation of the MiT/TFE family of transcription factors. The induction of lysosome biogenesis by ChA appears to partially protect macrophages from lipid-induced cytotoxicity. In sum, our data show that ChA is involved in the etiology of lysosome dysfunction and promotes the exocytosis of these organelles. This latter event is a new mechanism that may be important in the pathogenesis of atherosclerosis.

Original languageEnglish
Pages (from-to)284 - 307
JournalTraffic
Volume24
Issue number7
Early online date2023
DOIs
Publication statusPublished - Jul 2023

Keywords

  • cholesteryl hemiesters
  • lysosome dysfunction
  • lysosome exocytosis
  • oxidized low-density lipoproteins

Fingerprint

Dive into the research topics of 'Oxidized cholesteryl ester induces exocytosis of dysfunctional lysosomes in lipidotic macrophages'. Together they form a unique fingerprint.

Cite this