Macrophage Cholesterol Homeostasis and Atherogenesis: Critical Role of Intracellular Cholesteryl Ester Hydrolysis

Abstract

LDL. Macrophages express scavenger receptors, namely, scavenger receptor A (SR-A) and , that facilitate the uptake of modified LDL. Scavenger-receptor mediated uptake of modified LDL is largely unregulated and should be regarded as a mechanism that evolved to effectively clear modified lipoproteins from circulation and thus preventing the associated toxicity. Non-receptor mediated uptake pathways have recently been identified such as phagocytosis of aggregated LDL and macropinocytosis of native LDL that can also potentially contribute to lipid accumulation in macrophage foam cells. Cholesteryl esters (CE) associated with LDL are hydrolyzed in late endosomes/ lysosomes to free cholesterol (FC) which then traffics to and integrates into the plasma membrane. Excess membrane cholesterol and also a fraction of LDL-derived FC is transported to endoplasmic reticulum where it is re-esterified by acyl CoA:cholesterol acyltransferase-1 (ACAT1) and stored in cytoplasmic lipid droplets. While this re-esterification of cholesterol is initially beneficial to the cells in preventing the FC-associated cell toxicity, under conditions of unregulated or increased uptake of modified LDL, it leads to excessive accumulation of CE present as cytoplasmic lipid droplets giving the cells their characteristic "foamy" appearance. Cellular CE undergo constant cycle of hydrolysis and re-esterification (cholesteryl ester cycle) with a half life of 24h. Brown et al demonstrated for the first time that hydrolysis of stored CE is extra lysosomal and defined the "need" for a neutral cholesteryl ester hydrolase (CEH) (Brown et al, 1980) that can release FC from the lipid droplet associated CE which can either be re-esterified again by ACAT-1 or removed from the cells by extracellular acceptor-mediated cholesterol efflux. This ac c e p t o r m e d i a t e d F C e f f l u x i s t h e m a j o r mechanism for the removal of cellular cholesterol. Efflux of FC occurs either by aqueous diffusion or via several transporters namely ATP binding cassette transporter A1 (ABCA1) and ABCG1. Bidirectional flux of FC also occurs through scavenger receptor BI (SR-BI). Since FC is extremely hydrophobic, its efflux from the cells is coupled to its association with specific extracellular acceptors. Macrophages secrete apolipoprotein E (ApoE) and it is believed that ApoE serves as the extracellular acceptor for FC that is effluxed via aqueous diffusion pathway. Serum albumin, present in the interstitial fluid, also serves as an important acceptor for FC effluxed via non-transporter mediated pathways. Apolipoprotein A1 that is synthesized in the liver and secreted as minimally lipidated particle containing small amount of phospholipids is the acceptor for FC effluxed via ABCA1. After acquiring some amount of FC, ApoA1 can no longer accept FC from ABCA1. Bulk of FC efflux occurs via ABCG1 and ApoA1 with some FC or high density lipoprotein (HDL) serve as the extracellular acceptor for this process. A small amount of FC is also converted into 27-hydroxycholesterol which c...