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

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

ATHEROSCLEROSIS

ELSEVIER IRELAND LTD

Año: 2020

0021-9150

Background and aims: The transition of macrophage to foamcells is a major hallmark of early stage atherosclerotic lesions. This processis characterized by the accumulation of large cytoplasmic lipid droplets containinglarge quantities of cholesterol esters (CE), triacylglycerol (TAG) andphospholipid (PL). Although cholesterol and CE metabolism during foam cellformation has been broadly studied, little is known about the role of theglycerolipids (TAG and PL) in this context. Here we studied the contribution ofglycerolipid synthesis to lipid accumulation, focusing specifically on thefirst and rate-limiting enzyme of the pathway: glycerol-3-phosphateacyltransferase (GPAT).Methods: We used RAW 264.7 cells and bone marrow derivedmacrophages (BMDM) treated with oxidized LDL (oxLDL)Results: We showed that TAG synthesis is induced during themacrophage to foam cell transition. The expression and activity of GPAT3 andGPAT4 also increased during this process, and these two isoforms were requiredfor the accumulation of cell TAG and PL. Compared to cells from wildtype miceafter macrophage to foam cell transition, Gpat4-/-BMDM released more pro-inflammatory cytokines and chemokines, suggesting thatthe activity of GPAT4 could be associated with a decrease in the inflammatoryresponse, probably by sequestering signaling precursors into lipiddroplets.  Conclusions: Our results provide evidence that TAG synthesisdirected by GPAT3 and GPAT4 is required for lipid droplet formation and themodulation of the inflammatory response during the macrophage-foam celltransition.