マクロファージでのコレステロールエステルの蓄積過程におけるリン脂質代謝の役割 Involvement of Phospholipase A_2 in the Supply of Fatty Acids Required for Cholesterol Esterification Associated with Uptake of Oxidized Low-Density Lipoprotein in Macrophages

粥状動脈硬化症は,動脈の肥厚や脂質沈着に伴う血管機能の低下を主徴とする病変であり,狭心症や心筋梗塞などの急性冠症候群を引き起こす主因と考えられている.その発症や増悪化に関与する因子として,高脂血症に伴い血管内皮下で増大する低密度リポタンパク質(LDL),特に,その酸化成績体(酸化LDL)が知られている.酸化LDLは,血管内皮細胞,マクロファージ,血管平滑筋細胞などにおいて様々な細胞応答を誘起することで,粥状動脈硬化症の発症や進展に関与しており,その内,マクロファージの酸化LDLの貧食に伴う泡沫化は,初期病変の1つである血管内皮下での脂質の沈着を招く.このマクロファージの泡沫化は,細胞内でのコレステロールエステルの生成・蓄積に起因することから,コレステロールエステルの産生経路を解明することは,粥状動脈硬化症の進展過程を理解する上で意義があると考える.本稿では,このコレステロールエステルの生成過程に関して,リン脂質代謝,特に,リン脂質代謝酵素であるホスホリパーゼA_2(PLA_2)との関連性に焦点を当て,筆者の研究室で得られた知見を交えて概説したい.

The formation of foam cells, a critical event in the early stages of atherosclerosis, is associated with the uptake of oxidized low-density lipoprotein (oxLDL) by macrophages and the subsequent accumulation of cholesterol ester formed by the catalytic action of acyl-CoA: cholesterol acyltransferase (ACAT). Although free cholesterol, a substrate for ACAT, is supplied from the intracellular cholesterol pool, little is known about the pathways involved in the supply of fatty acids, precursors for fatty acyl-CoA as another substrate for ACAT. Our recent studies were undertaken to examine the possible involvement of phospholipase A_2 (PLA_2) in the supply of fatty acids required for the cholesterol esterification. In mouse peritoneal macrophages and RAW264.7 macrophages, oxLDL induced the liberation of fatty acids from membrane phospholipids to increase cholesterol ester having the fatty acids as an acyl chain. The changes in these lipids were suppressed by the inhibition of cytosolic PLA_2 (cPLA_2). Although oxLDL did not affect the activity or amounts of cPLA_2, preincubation with oxLDL enhanced the release of fatty acids induced by Ca^<2+> ionophore, which accelerates the hydrolytic action of cPLA_2. We further observed that oxLDL induced the generation of ceramide through the de novo synthesis. Exogenous ceramide and 13-hydroxyoctadecadienoic acid, an oxidized lipid in oxLDL particles, also stimulated fatty acid release. Based on these findings, we propose that oxLDL activates cPLA_2 to supply fatty acids required for the cholesterol esterification, through the acceleration of the hydrolytic action of cPLA_2 by endogenous ceramide and by oxidized lipids in oxLDL particles in macrophages.