Table 1.

Summary of selected strategies to increase macrophage reverse cholesterol transport

Therapeutic strategy	Effect on HDL Levels	Effect on murine macrophage RCT	Effect on atherosclerosis	Rationale	Limitations	Stage of clinical development
Strategy #1: Increase macrophage cholesterol efflux
LXR agonism	Variable	Increased	Decreased	Upregulate ABCA1- and ABCG1-mediated efflux; may also increase intestinal secretion	Induction of hepatic steatosis, particularly with nonselective agonists	Early clinical
Strategy #2: Increase HDL acceptor number and functionality
PPARα agonism	Variable	Increased	Unknown	Stimulate apoA-I production/turnover; also increases cellular efflux	Nonspecific effects, safety concerns in humans	Early clinical
ApoA-I/reconstituted HDL infusions	Increased	Unknown	Decreased	Promote RCT and enhance plaque stability via short-term infusion	Limited human efficacy data; need for intravenous administration	Early clinical
ApoA-I mimetic peptides	None	Increased	Decreased	Recapitulate beneficial effects of full-length apoA-1 via oral administration	Modest oral bioavailability, no human efficacy data	Early clinical
CETP inhibition	Increased	Variable	Unknown	Prevent transfer of cholesteryl esters from HDL to apoB-containing lipoproteins, increasing HDL levels	Unknown effects on RCT, failure in one large phase 3 clinical trial	Phase 3 clinical trials
Endothelial lipase inhibition	Increased	Unknown	Unknown	Decrease hydrolysis of HDL phospholipids, slowing HDL catabolism	Unknown effects on RCT, paucity of small molecule inhibitors	Preclinical
Strategy #3: Increase hepatic uptake and intestinal excretion
Ezetemibe	None	Increased	Decreased	Limit intestinal cholesterol reabsorption	Limited data demonstrating improved clinical outcomes in humans	In clinical use
PPARδ agonism	Increased	Increased	Unknown	Limit intestinal cholesterol reabsorption, may improve clearance of postprandial triglycerides	Unknown mechanism of increasing HDL levels, minimal data in humans	Early clinical
Fish oil	Increased	Increased	Decreased	Enhance hepatic cholesterol excretion via ABCG5/ABCG8 transporters, decrease intestinal cholesterol absorption	Unclear if clinical benefit is related to increased RCT	In clinical use

ABC ATP-binding cassette, apo apolipoprotein, CETP cholesteryl ester transfer protein, HDL high-density lipoprotein, LXR liver X receptor, PPAR peroxisome proliferator-activated receptor, RCT reverse cholesterol transport