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Future Therapeutic Directions in Reverse Cholesterol Transport

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Abstract

Despite a robust inverse association between high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease, the development of new therapies based on pharmacologic enhancement of HDL metabolism has proven challenging. Emerging evidence suggests that static measurement of HDL levels has inherent limitations as a surrogate for overall HDL functionality, particularly with regard to the rate of flux through the macrophage reverse cholesterol transport (RCT) pathway. Recent research has provided important insight into the molecular underpinnings of RCT, the process by which excess cellular cholesterol is effluxed from peripheral tissues and returned to the liver for ultimate intestinal excretion. This review discusses the critical importance and current strategies for quantifying RCT flux. It also highlights therapeutic strategies for augmenting macrophage RCT via three conceptual approaches: 1) improved efflux of cellular cholesterol via targeting the macrophage; 2) enhanced cholesterol efflux acceptor functionality of circulating HDL; and 3) increased hepatic uptake and biliary/intestinal excretion.

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Acknowledgment

This work was supported by P01-HL22633 from the National Heart, Lung, and Blood Institute; an Alternative Drug Discovery Initiative award to the University of Pennsylvania from GlaxoSmithKline, and a Doris Duke Charitable Foundation Distinguished Clinical Scientist Award (to DJR).

Disclosure

Dr. Rader serves as a consultant to several companies that market or are developing therapies targeting HDL or RCT, including Abbott, AstraZeneca, Bristol-Myers-Squibb, Eli Lilly, Johnson & Johnson, Merck & Co, Novartis, and Resverlogix. No other potential conflicts of interest relevant to this article were reported.

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  1. Institute for Translational Medicine and Therapeutics and Cardiovascular Institute, University of Pennsylvania, Philadelphia, PA, USA

    Amit V. Khera

  2. University of Pennsylvania School of Medicine, 654 BRBII/III, 421 Curie Blvd, Philadelphia, PA, 19104, USA

    Daniel J. Rader

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Khera, A.V., Rader, D.J. Future Therapeutic Directions in Reverse Cholesterol Transport. Curr Atheroscler Rep 12, 73–81 (2010). https://doi.org/10.1007/s11883-009-0080-0

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