Free Cholesterol Bioavailability and Atherosclerosis

Authors

Rei J Abe
Jun-Ichi Abe
Minh T H Nguyen
Elizabeth A Olmsted-Davis
Abrar Mamun
Priyanka Banerjee
John P Cooke
Longhou Fang
Henry Pownall
Nhat-Tu Le

Publication Date

5-1-2022

Journal

Current Atherosclerosis Reports

Abstract

Purpose of review: As both a cholesterol acceptor and carrier in the reverse cholesterol transport (RCT) pathway, high-density lipoprotein (HDL) is putatively atheroprotective. However, current pharmacological therapies to increase plasma HDL cholesterol (HDL-c) concentration have paradoxically failed to prevent or reduce atherosclerosis and cardiovascular disease (CVD). Given that free cholesterol (FC) transfer between surfaces of lipoproteins and cells is reversible, excess plasma FC can be transferred to the cells of peripheral tissue sites resulting in atherosclerosis. Here, we summarize potential mechanisms contributing to this paradox and highlight the role of excess free cholesterol (FC) bioavailability in atherosclerosis vs. atheroprotection.

Recent findings: Recent findings have established a complex relationship between HDL-c concentration and atherosclerosis. Systemic scavenger receptor class B type 1 (SR-B1) knock out (KO) mice exhibit with increased diet-induced atherosclerosis despite having an elevated plasma HDL-c concentration compared to wild type (WT) mice. The greater bioavailability of HDL-FC in SR-B1 vs. WT mice is associated with a higher FC content in multiple cell types and tissue sites. These results suggest that dysfunctional HDL with high FC bioavailability is atheroprone despite high HDL-c concentration. Past oversimplification of HDL-c involvement in cholesterol transport has led to the failures in HDL targeted therapy. Evidence suggests that FC-mediated functionality of HDL is of higher importance than its quantity; as a result, deciphering the regulatory mechanisms by which HDL-FC bioavailability can induce atherosclerosis can have far-reaching clinical implications.

Keywords

Animals, Atherosclerosis, Cholesterol, Cholesterol, HDL, Humans, Lipoproteins, HDL, Mice, Mice, Knockout, Scavenger Receptors, Class B, Cardiovascular disease, Free cholesterol, High-density lipoprotein, Scavenger receptor class B type 1, Reverse cholesterol transport

DOI

10.1007/s11883-022-01011-z

PMID

35332444

PMCID

PMC9050774\

PubMedCentral® Posted Date

3-25-2022

PubMedCentral® Full Text Version

Post-print

Published Open-Access

yes