Cholesteryl Hemiazelate Present in Cardiovascular Disease Patients Causes Lysosome Dysfunction in Murine Fibroblasts

Area of Science:

• Cardiovascular Biology
• Cellular Pathophysiology
• Atherosclerosis Research

Background:

• Fibroblasts play a critical role in atherosclerosis development and plaque formation.
• Oxidized lipids, including cholesteryl hemiesters (ChE), accumulate in atherosclerotic lesions.
• Cholesteryl hemiazelate (ChA), a prevalent ChE, impairs lysosome function in macrophages and vascular smooth muscle cells.

Purpose of the Study:

• To investigate the impact of ChA on fibroblast lysosome function and cellular homeostasis.
• To elucidate the downstream consequences of ChA-induced lysosomal dysfunction in fibroblasts.
• To determine if ChA-induced fibroblast dysfunction contributes to atherosclerosis pathogenesis.

Main Methods:

• Treatment of human fibroblasts with ChA.
• Microscopic analysis of lysosomal morphology and lipid accumulation.
• Assessment of lysosome biogenesis, TFE3 transcription, autophagy, mTORC1 activation, and fibroblast apoptosis.

Main Results:

• ChA treatment caused perinuclear accumulation of enlarged, lipid-laden lysosomes in fibroblasts.
• De novo lysosome biogenesis was not induced, with only minor TFE3 upregulation.
• Autophagy was inhibited, likely via mTORC1 activation, leading to fibroblast apoptosis.

Conclusions:

• ChA induces lysosomal dysfunction and apoptosis in fibroblasts, similar to its effects on other cell types.
• Impaired lysosome function and autophagy in fibroblasts represent a novel mechanism contributing to atherosclerosis.
• Targeting ChA-mediated cellular damage in fibroblasts may offer a therapeutic strategy for atherosclerosis.