Itaconate alleviates cholesterol burden via ABCA1 stabilization and cholesterol efflux

Area of Science:

• Cardiovascular Research
• Metabolic Disease
• Immunomodulation

Background:

• Atherosclerosis involves plaque growth and instability, influenced by immune cells.
• Itaconate (ITA), a TCA metabolite, shows immunomodulatory effects on atherosclerotic plaques.
• ITA's role in regulating lipid metabolism within atherosclerosis remains largely unexplored.

Purpose of the Study:

• Investigate ITA's effects on lipid metabolism in atherosclerotic foam cells/macrophages.
• Utilize plaque-targeting ITA-conjugated nanoparticles (ITA-LNPs) for targeted delivery.
• Elucidate ITA's mechanism involving ABCA1 stabilization and triglyceride metabolism.

Main Methods:

• Administered ITA-LNPs or control LNPs to Apoe-/- mice on a high-cholesterol diet.
• Analyzed ITA-LNP biodistribution and atherosclerotic plaque burden.
• Treated bone marrow-derived macrophages (BMDMs) and RAW 264.7 cells with ITA-LNPs under various lipid conditions to assess lipid metabolism and ABCA1 regulation.

Main Results:

• ITA-LNPs significantly upregulated ABCA1 protein levels in vivo and in vitro.
• ITA-LNPs prevented ABCA1 decay via the HO-1-calpain pathway, enhancing cholesterol efflux.
• ITA treatment reduced lipid burden and increased fatty acid metabolism by enhancing citrate shuttling.

Conclusions:

• ITA-LNPs effectively regulate lipid metabolism in atherosclerosis.
• ITA promotes triglyceride catabolism and cholesterol efflux in macrophages.
• ITA-LNPs represent a potential therapeutic strategy for atherosclerosis management.