Brothers in Arms: ABCA1- and ABCG1-Mediated Cholesterol Efflux as Promising Targets in Cardiovascular Disease Treatment

Abstract

Atherosclerosis is a leading cause of cardiovascular disease worldwide, and hypercholesterolemia is a major risk factor. Preventive treatments mainly focus on the effective reduction of low-density lipoprotein cholesterol, but their therapeutic value is limited by the inability to completely normalize atherosclerotic risk, probably due to the disease complexity and multifactorial pathogenesis. Consequently, high-density lipoprotein cholesterol gained much interest, as it appeared to be cardioprotective due to its major role in reverse cholesterol transport (RCT). RCT facilitates removal of cholesterol from peripheral tissues, including atherosclerotic plaques, and its subsequent hepatic clearance into bile. Therefore, RCT is expected to limit plaque formation and progression. Cellular cholesterol efflux is initiated and propagated by the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. Their expression and function are expected to be rate-limiting for cholesterol efflux, which makes them interesting targets to stimulate RCT and lower atherosclerotic risk. This systematic review discusses the molecular mechanisms relevant for RCT and ABCA1 and ABCG1 function, followed by a critical overview of potential pharmacological strategies with small molecules to enhance cellular cholesterol efflux and RCT. These strategies include regulation of ABCA1 and ABCG1 expression, degradation, and mRNA stability. Various small molecules have been demonstrated to increase RCT, but the underlying mechanisms are often not completely understood and are rather unspecific, potentially causing adverse effects. Better understanding of these mechanisms could enable the development of safer drugs to increase RCT and provide more insight into its relation with atherosclerotic risk.Significance Statement--Hypercholesterolemia is an important risk factor of atherosclerosis, which is a leading pathological mechanism underlying cardiovascular disease. Cholesterol is removed from atherosclerotic plaques and subsequently cleared by the liver into bile. This transport is mediated by high-density lipoprotein particles, to which cholesterol is transferred via ATP-binding cassette transporters ABCA1 and ABCG1. Small-molecule pharmacological strategies stimulating these transporters may provide promising options for cardiovascular disease treatment.

Active cholesterol 20 years on

“…Cholesterol is translocated from plasma membranes to extracellular acceptors in the blood, bile and intestines by a family of ABC ATPases. While the structures and sterol binding motifs of some of the ABC transporters have been delineated, their molecular mechanisms and the pathways by which the sterol is exported have not been resolved in detail 107‐110 . One might imagine that these proteins simply pump excess active cholesterol from the plasma membrane; however, it appears in some cases that they utilize metabolic energy to activate cholesterol which then exits passively.…”

“…In addition, ABCG1 provides (active?) cholesterol to nascent HDL particles as they are being assembled by ABCA1 110,113 …”

<p>Ox-LDL Causes Endothelial Cell Injury Through ASK1/NLRP3-Mediated Inflammasome Activation via Endoplasmic Reticulum Stress</p>

“…Of the mechanisms that have been described, pathway included ABCA1/ABCG1 was widely studied. [16][17][18][19] As far as we know, cholesterol efflux transport relies on some specific proteins, such as ABCA1 and ABCG1, which has been regarded as gatekeeper for mediating tissue cholesterol. 20 ABCA1 and ABCG1 present additional activities during enhancing process of reverse cholesterol transport in vivo.…”

“…22 Frambach et al indicate that small molecule pharmacological strategies targeting ABCA1 and ABCG1 can be recommended as a promising option for cardiovascular disease. 16 Therefore, we also wondered that whether ABCA1 and ABCG1 can be mediated by endoplasmic reticulum stress response to facilitate cholesterol efflux in endothelial cell.…”

The crosstalk of ABCA1 and ANXA1: a potential mechanism for protection against atherosclerosis

“…ANXA1 secretion has been found to occur in many types of cells, including monocytes/macrophages, mast cells, epithelial cells, folliculo-stellate (FS) cells, neutrophils, and astrocytes (Purvis et al 2019b ; Sugimoto et al 2016 ). It has also been detected in a variety of tissues, such as heart, artery, skeletal muscle, small intestine, colon, adipose, kidney, liver, lung, spleen, stomach, pancreas, skin, brain, and prostate tissue, wherein ABCA1 is strongly expressed (Frambach et al 2020 ). In addition, the expression of ABCA1 and ANXA1 are positively correlated in plaque macrophages with oxidized low-density lipoprotein (oxLDL) and monocytes of hypercholesterolemic pigs (Geeraert et al 2007 ; Orekhov et al 2018 ).…”