Macrophage-mediated cholesterol handling in atherosclerosis

Abstract

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 (oxLDL). Several scavenger receptors (SR), including CD36, SR-A1 and lectin-like oxLDL receptor-1 (LOX-1), mediate oxLDL uptake. In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In the endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase-1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out-flowed from macrophages by cholesterol ATP-binding cassette (ABC) transporters ABCA1 and ABCG1 and SR-BI. In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.

Keywords: atherogenesis; atherosclerosis; cholesterol; foam cells; lipoproteins; macrophages.

Figure 1

Cholesterol metabolism in macrophages. Macrophages engulf oxidized cholesterol (oxLDL) with help of several scavenger receptors (SR) including CD36, SR‐A1, and lectin‐like oxLDL receptor‐1 (LOX‐1). In late endosomes/lysosomes of macrophages, oxLDL are catabolysed. Lysosomal acid lipase (LAL) hydrolyses cholesterol esters that are enriched in LDL to free cholesterol and free fatty acids. In endoplasmic reticulum (ER), acyl coenzyme A: cholesterol acyltransferase‐1 (ACAT1) in turn catalyses esterification of cholesterol to store cholesterol esters as lipid droplets in the ER of macrophages. Neutral cholesteryl ester hydrolases nCEH and NCEH1 are involved in a secondary hydrolysis of cholesterol esters to liberate free cholesterol that could be then out‐flowed from macrophages by cholesterol ATP‐binding cassette (ABC) transporters ABCA1 and ABCG1 and scavenger receptor SR‐BI. The main acceptors of free cholesterol from ABCG1 and SR‐BI are high density lipoprotein (HDL) and from ABCA1 is apolipoprotein A1 (ApoA1). In atherosclerosis, disruption of lipid homoeostasis in macrophages leads to cholesterol accumulation and formation of foam cells.

Figure 2

Electron micrograph showing a macrophage foam cell, the cytoplasm of which filled with a large number of ‘lipid droplets’ (L). N – nucleus. Atherosclerotic plaque tissue specimen of the human aorta. Transmission electron microscopy (TEM); scale bar = 5 μm.

Figure 3

Formation of cholesterol crystals in the cytoplasm of a foam cell (A and B). (B) It is a detail of (A). L ‐ ‘lipid droplet’. In (A), arrows show the plasma membrane of the foam cells. In (B), arrows show cholesterol crystals. Atherosclerotic plaque tissue specimen of the human aorta. TEM; scale bar = 1 μm (A).

Figure 4

Cholesterol crystals (C) and ‘lipid droplets’ (L) located in the extracellular matrix of an atherosclerotic plaque of the human aorta. TEM; scale bar = 1 μm.