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Review
. 2022 Jun;21(11):1121-1139.
doi: 10.1080/15384101.2022.2042777. Epub 2022 Feb 22.

Molecular mechanisms for ABCA1-mediated cholesterol efflux

Lei Chen  1 , Zhen-Wang Zhao  2 , Peng-Hui Zeng  3 , Ying-Jie Zhou  3 , Wen-Jun Yin  3
Affiliations
Review

Molecular mechanisms for ABCA1-mediated cholesterol efflux

Lei Chen et al. Cell Cycle. 2022 Jun.

Abstract

The maintenance of cellular cholesterol homeostasis is essential for normal cell function and viability. Excessive cholesterol accumulation is detrimental to cells and serves as the molecular basis of many diseases, such as atherosclerosis, Alzheimer's disease, and diabetes mellitus. The peripheral cells do not have the ability to degrade cholesterol. Cholesterol efflux is therefore the only pathway to eliminate excessive cholesterol from these cells. This process is predominantly mediated by ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein. ABCA1 is known to transfer intracellular free cholesterol and phospholipids to apolipoprotein A-I (apoA-I) for generating nascent high-density lipoprotein (nHDL) particles. nHDL can accept more free cholesterol from peripheral cells. Free cholesterol is then converted to cholesteryl ester by lecithin:cholesterol acyltransferase to form mature HDL. HDL-bound cholesterol enters the liver for biliary secretion and fecal excretion. Although how cholesterol is transported by ABCA1 to apoA-I remains incompletely understood, nine models have been proposed to explain this effect. In this review, we focus on the current view of the mechanisms underlying ABCA1-mediated cholesterol efflux to provide an important framework for future investigation and lipid-lowering therapy.

Keywords: ABCA1; apoA-I; cholesterol; nHDL; phospholipids.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Topological diagram of ABCA1.
Figure 2.
Figure 2.
Schematic illustration of the channel trafficking model.
Figure 3.
Figure 3.
Schematic illustration of two-step process model.
Figure 4.
Figure 4.
Schematic illustration of mushroom-like protrusion model.
Figure 5.
Figure 5.
Schematic illustration of V-ATPase-induced apoA-I unfolding model.
Figure 6.
Figure 6.
Schematic illustration of PIP2-induced apoA-I unfolding model.
Figure 7.
Figure 7.
Schematic illustration of ABCA1 dimerization model.
Figure 8.
Figure 8.
Schematic illustration of apoA-I-free vesicle model.
Figure 9.
Figure 9.
Schematic illustration of sequential apoA-I addition model.
Figure 10.
Figure 10.
Schematic illustration of the retroendocytosis model.
See this image and copyright information in PMC

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