Triacylglycerol synthesis directed by glycerol-3-phosphate acyltransferases -3 and -4 is required for lipid droplet formation and the modulation of the inflammatory response during macrophage to foam cell transition

PELLON-MAISON, MAGALI; GONZALEZ-BARO, MARIA R.; GONZALEZ, MARINA C.; QUIROGA, IVANA Y.; COLEMAN, ROSALIND A.

ATHEROSCLEROSIS

ELSEVIER IRELAND LTD

Año: 2020

0021-9150

Background and aims: The transition of macrophage to foam cells is a major hallmarkof early stage atherosclerotic lesions. This process is characterized by theaccumulation of large cytoplasmic lipid droplets containing large quantities ofcholesterol esters (CE), triacylglycerol (TAG) and phospholipid (PL). Althoughcholesterol and CE metabolism during foam cell formation has been broadly studied,little is known about the role of the glycerolipids (TAG and PL) in this context. Here westudied the contribution of glycerolipid synthesis to lipid accumulation, focusingspecifically on the first and rate-limiting enzyme of the pathway: glycerol-3-phosphateacyltransferase (GPAT).Methods: We used RAW 264.7 cells and bone marrow derived macrophages (BMDM)treated with oxidized LDL (oxLDL)Results: We showed that TAG synthesis is induced during the macrophage to foam celltransition. The expression and activity of GPAT3 and GPAT4 also increased during thisprocess, and these two isoforms were required for the accumulation of cell TAG andPL. Compared to cells from wildtype mice after macrophage to foam cell transition,Gpat4 -/- BMDM released more pro-inflammatory cytokines and chemokines,suggesting that the activity of GPAT4 could be associated with a decrease in theinflammatory response, probably by sequestering signaling precursors into lipiddroplets.Conclusions: Our results provide evidence that TAG synthesis directed by GPAT3 andGPAT4 is required for lipid droplet formation and the modulation of the inflammatoryresponse during the macrophage-foam cell transition.