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Novel Approaches for HDL-Directed Therapies

  • Jacques Genest
  • Hong Y. Choi
Nonstatin Drugs (E. deGoma, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Nonstatin Drugs

Abstract

Purpose of Review

High-density lipoproteins (HDL) are thought to exert a protective role against atherosclerosis. The measurement of the cholesterol mass within HDL (HDL-C) represents a good biomarker of cardiovascular health, but HDL-C appears to be a poor therapeutic target. Here, we discuss new targets for the development of HDL-directed therapies.

Recent Findings

Among cardio-protective functions of HDL particles, the ability of HDL to remove cholesterol from cells involved in the early stages of atherosclerosis is considered one of the most important functions. This process, termed “HDL biogenesis,” is initiated by the formation of highly specialized plasma membrane micro-domains by the ATP-binding cassette transporter A1 (ABCA1) and the binding of apolipoproteins (apo) such as apoA-I, the major protein moiety of HDL, to the micro-domains. Although early strategies aimed at increasing HDL biogenesis by upregulating ABCA1 or apoA-I gene expression have not met with clinical success, recent advances in understanding transcriptional, post-transcriptional, and post-translational regulatory pathways propose new targets for the promotion of HDL biogenesis. We have recently reported that a novel apoA-I-binding protein desmocollin 1 (DSC1) prevents HDL biogenesis and that inhibition of apoA-I-DSC1 interactions promotes HDL biogenesis by stabilizing ABCA1. This new HDL regulation pathway nominates DSC1 as an attractive pharmacological target.

Summary

In the absence of clinically useful therapy to increase HDL biogenesis, finding novel targets to unlock the therapeutic potential of HDL is highly desired. Modulation of apoA-I-DSC1 interactions may be a viable strategy.

Keywords

Atherosclerosis High-density lipoprotein Apolipoprotein A-I Cholesterol Desmocollin 1 ABCA1 

Notes

Funding

This work was supported by a grant from the Canadian institutes of Health Research (CIHR MOP 15042 JG).

Compliance with Ethical Standards

Conflict of Interest

Jacques Genest and Hong Y. Choi declare no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References

Papers of particular interest, published recently, have been highlighted as: Of importance •• Of major importance

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© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.The Research Institute of the McGill University Health CenterMontrealCanada

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