Synaptic PKC is a downstream effector of PLD during iron-induced oxidative stress. Effect of aging

Abstract

Type-2 diabetes and obesity are characterized by an excessive accumulation of triacylglycerols (TAG) partially caused by a deregulation of glycerol-3-phosphate acyltransferases (GPATs) that catalyze the first step in de novo glycerolipid synthesis, and carnitine palmitoyl transferase 1 (CPT1) that regulates fatty acid oxidization. In order to study the roles of these enzymes in monocyte-macrophage(MP)-foam-cell transition (a model of TAG accumulation during atherogenesis) we tested their expression by qRT-PCR in the murine MP RAW264 and the human THP-1 monocyte cell lines differentiated into foam cells by oxidized LDL (oxLDL) and into MP by PMA, respectively. Mitochondrial GPAT1 and 2 expressions did not change in either model. We then analyzed the ER isoforms GPAT3 and 4. Interestingly, only GPAT3 expression significantly increased in monocyte to MP transition. These results were consistent with GPAT activity assays, since N- ethylmaleimide (NEM) sensitive activity (GPAT2, 3 and 4) but not NEM resistant activity (GPAT1) increased after oxLDL treatment. We could also prove that CPT1a was up-regulated during RAW264 cell differentiation to foam cells while a significant decrease was observed in the human MP derived from THP1 monocytes, suggesting that β-oxidation is not that active in MP, consistently with the anaerobic metabolism hallmark of M1 pro-inflammatory M P.