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Review
. 2019 Jan-Mar;15(1):47-54.
doi: 10.14797/mdcj-15-1-47.

Revisiting Reverse Cholesterol Transport in the Context of High-Density Lipoprotein Free Cholesterol Bioavailability

Corina Rosales  1   2 , Baiba K Gillard  1   2 , Bingqing Xu  3 , Antonio M Gotto Jr  1   2 , Henry J Pownall  1   2
Affiliations
Review

Revisiting Reverse Cholesterol Transport in the Context of High-Density Lipoprotein Free Cholesterol Bioavailability

Corina Rosales et al. Methodist Debakey Cardiovasc J. 2019 Jan-Mar.

Abstract

Dysregulated free cholesterol (FC) metabolism has been implicated in nearly all stages of atherosclerosis, the underlying cause of most cardiovascular disease. According to a widely cited model, the burden of macrophage FC in the arterial wall is relieved by transhepatic reverse cholesterol transport (RCT), which comprises three successive steps: (1) macrophage FC efflux to high-density lipoprotein (HDL) and/or its major protein, apolipoprotein AI; (2) FC esterification by lecithin:cholesterol acyltransferase (LCAT); and (3) HDL-cholesteryl ester (CE) uptake via the hepatic HDL-receptor, scavenger receptor class B type 1 (SR-B1). Recent studies have challenged the validity of this model, most notably the role of LCAT, which appears to be of minor importance. In mice, most macrophage-derived FC is rapidly cleared from plasma (t1/2 < 5 min) without esterification by hepatic uptake; the remainder is taken up by multiple tissue and cell types, especially erythrocytes. Further, some FC is cleared by the nonhepatic transintestinal pathway. Lastly, FC movement among lipid surfaces is reversible, so that a higher-than-normal level of HDL-FC bioavailability-defined by high plasma HDL levels concurrent with a high mol% HDL-FC-leads to the transfer of excess FC to cells in vivo. SR-B1-/- mice provide an animal model to study the mechanistic consequences of high HDL-FC bioavailability that provokes atherosclerosis and other metabolic abnormalities. Future efforts should aim to reduce HDL-FC bioavailability, thereby reducing FC accretion by tissues and the attendant atherosclerosis.

Keywords: atherogenesis; cholesterol; free cholesterol bioavailability; high-density lipoproteins; lipid metabolism; reverse cholesterol transport.

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Conflict of interest statement

Conflict of Interest Disclosure: Dr. Gotto is a consultant for Esperion and KOWA Pharmaceuticals America, Inc. and is on the Data Safety Monitoring Board for Ionis Pharmaceuticals.

Figures

Figure 1.
Figure 1.
(A) Hazard ratio by high-density lipoprotein cholesterol (HDL-C) quintile. (B) Correlation of HDL percentile with HDL-C level; red bar denotes the range for the “optimal” HDL-C level from A. MetS: metabolic syndrome; DysHDL: dysfunctional HDL
Figure 2.
Figure 2.
Traditional reverse cholesterol transport model comprises three steps: (1) macrophage free cholesterol efflux to apolipoprotein AI via the ATP-binding cassette transporter A1 (ABCA1) yields nascent high-density lipoprotein (nHDL); (2) nHDL esterification by lecithin:cholesterol acyltransferase (LCAT) gives spherical HDL; and (3) selective hepatic uptake of HDL cholesterol ester. SR-B1: scavenger receptor class B type 1
Figure 3.
Figure 3.
Cell free cholesterol (FC), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR), and acyl-coenzyme A:cholesterol acyltransferase (ACAT) as a function of reassembled high-density lipoprotein (rHDL) mol% FC as labeled.
Figure 4.
Figure 4.
Comparison of free cholesterol (FC) transfer from wild type (WT) and scavenger receptor class B type 1 (SR-B1)−/− high-density lipoprotein (HDL) mice. The initially higher mol% FC in SR-B1−/− versus WT HDL results in more transfer to LDL at equilibrium (t = 20 min). LP: lipoprotein; PL: phospholipid
Figure 5.
Figure 5.
A revised reverse cholesterol transfer (RCT) model. In this model, (1) free cholesterol (FC) efflux to apolipoprotein AI (apoAI) via the ATP-binding cassette transporter A1 (ABCA1) forms nascent high-density lipoprotein (nHDL), which (2) transfers some of its FC to HDL within the plasma compartment (defined by the rectangle). (3, 4) FC transfers to the liver via scavenger receptor class B type 1 (SR-B1) and spontaneous transfer (5) and to erythrocytes. Concurrently, (6) some apoAI is released from nHDL and HDL for another cycle of efflux. PL: phospholipid
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