Oxidized LDL-induced endolysosomal phospholipidosis and enzymatically modified LDL-induced foam cell formation determine specific lipid species modulation in human macrophages

Recruitment of circulating monocytes and formation of macrophage foam cells in the arterial intima are characteristic features of atherogenesis. Foam cells are formed by cellular uptake and storage of atherogenic lipoproteins, including oxidized LDL (oxLDL) and enzymatically modified LDL (eLDL). Dissection of oxLDL- and eLDL-induced cellular phenotypes indicates that these two LDL-modifications are coupled with two fundamentally different cellular responses in macrophages. Oxidized LDL preferentially up-regulates scavenger receptors required for its internalization, induces preferential lipid storage in the acidic compartment resembling drug-induced endolysosomal phospholipidosis, parallel with increased cellular content of the endolysosomal signature lipid bis(monoacylglycero)phosphate, pro-apoptotic signalling and appearance of ceramide-enriched surface membrane microdomains. By contrast, challenge of macrophages by eLDL leads to expanded cholesterol- and sphingomyelin-enriched surface membrane microdomains, up-regulation of diverse pattern recognition receptors required for phagocytosis of eLDL, parallel with extensive lipid droplet formation, increased endoplasmic reticulum (ER)-stress and membrane contact site formation for interorganelle trafficking and signalling, and enhanced cellular content of the mitochondrial lipid cardiolipin.This review focuses on biological activities of oxLDL and eLDL in human macrophages, and discusses some lipidomic considerations related to foam cell formation and phospholipidosis.

► Dissection of oxLDL-induced endosomal, and eLDL-driven lipid droplet storage in macrophages.
► Oxidized LDL induces endolysosomal phospholipidosis and increases cellular BMP content.
► Cellular eLDL challenge leads to lipid droplet storage and expansion of cardiolipin content.
► The phosphatidylglycerol – BMP – cardiolipin axis provides signature lipids for cellular storage.