Macrophage‐mediated cholesterol handling in atherosclerosis

<jats:title>Abstract</jats:title><jats:p>Formation of foam cells is a hallmark at the initial stages of atherosclerosis. Monocytes attracted by pro‐inflammatory stimuli attach to the inflamed vascular endothelium and penetrate to the arterial intima where they differentiate to macrophages. Intimal macrophages phagocytize oxidized low‐density lipoproteins (ox<jats:styled-content style="fixed-case">LDL</jats:styled-content>). Several scavenger receptors (<jats:styled-content style="fixed-case">SR</jats:styled-content>), including <jats:styled-content style="fixed-case">CD</jats:styled-content>36, <jats:styled-content style="fixed-case">SR</jats:styled-content>‐A1 and lectin‐like ox<jats:styled-content style="fixed-case">LDL</jats:styled-content> receptor‐1 (<jats:styled-content style="fixed-case">LOX</jats:styled-content>‐1), mediate ox<jats:styled-content style="fixed-case">LDL</jats:styled-content> uptake. In late endosomes/lysosomes of macrophages, ox<jats:styled-content style="fixed-case">LDL</jats:styled-content> are catabolysed. Lysosomal acid lipase (<jats:styled-content style="fixed-case">LAL</jats:styled-content>) hydrolyses cholesterol esters that are enriched in <jats:styled-content style="fixed-case">LDL</jats:styled-content> to free cholesterol and free fatty acids. In the endoplasmic reticulum (<jats:styled-content style="fixed-case">ER</jats:styled-content>), acyl coenzyme A: cholesterol acyltransferase‐1 (<jats:styled-content style="fixed-case">ACAT</jats:styled-content>1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the <jats:styled-content style="fixed-case">ER</jats:styled-content> of macrophages. Neutral cholesteryl ester hydrolases <jats:styled-content style="fixed-case">nCEH</jats:styled-content> and <jats:styled-content style="fixed-case">NCEH</jats:styled-content>1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out‐flowed from macrophages by cholesterol <jats:styled-content style="fixed-case">ATP</jats:styled-content>‐binding cassette (<jats:styled-content style="fixed-case">ABC</jats:styled-content>) transporters <jats:styled-content style="fixed-case">ABCA</jats:styled-content>1 and <jats:styled-content style="fixed-case">ABCG</jats:styled-content>1 and <jats:styled-content style="fixed-case">SR</jats:styled-content>‐<jats:styled-content style="fixed-case">BI</jats:styled-content>. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.</jats:p>