Faculty Collaboration Database

Why targeting HDL should work as a therapeutic tool, but has not. J Cardiovasc Pharmacol 2013 Sep;62(3):239-46

Date

06/08/2013

Pubmed ID

23743767

Pubmed Central ID

PMC3772973

DOI

10.1097/FJC.0b013e31829d48a5

Scopus ID

2-s2.0-84884671413 (requires institutional sign-in at Scopus site)   30 Citations

Abstract

Atherosclerosis is one of the most common causes of death and disability in the United States today despite the availability of statins, which reduce hyperlipidemia, a risk factor that predisposes individuals to this disease. Epidemiology of human populations has overwhelmingly demonstrated an inverse correlation between the concentration of plasma high-density lipoprotein (HDL) cholesterol (HDL-C) and the likelihood of developing cardiovascular disease (CVD). Decades of observations and mechanistic studies suggest that one protective function of HDL is its central role in reverse cholesterol transport. In this pathway, the ATP-binding cassette transporter A1 releases intracellular cholesterol, which is packaged with apolipoprotein A-I (apoA-I) into nascent HDL particles and released from the plasma membrane. Further lipidation and maturation of HDL occur in plasma with the eventual uptake by the liver where cholesterol is removed. It is generally accepted that CVD risk can be reduced if plasma HDL-C levels are elevated. Several different pharmacological approaches have been tried; the most popular approach targets the movement of cholesteryl ester from HDL to triglyceride-rich particles by cholesteryl ester transfer protein. Inhibition of cholesteryl ester transfer protein increases plasma HDL-C concentration; however, beneficial effects have yet to be demonstrated, likely the result of off-target effects. These revelations have led to a reevaluation of how elevating HDL concentration could decrease risk. A recent, landmark study showed that the inherent cholesterol efflux capacity of an individual's plasma was a better predictor of CVD status than overall HDL-C concentration. Even more provocative are recent studies showing that apoA-I, the principle protein component of HDL modulates cellular inflammation and oxidation. The following will review all these potential routes explaining how HDL apoA-I can reduce the risk of CVD.

Author List

Sorci-Thomas MG, Thomas MJ

Authors

Mary Sorci Thomas PhD Professor in the Medicine department at Medical College of Wisconsin
Michael J. Thomas PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apolipoprotein A-I
Atherosclerosis
Cholesterol
Drug Resistance
Humans
Hypoalphalipoproteinemias
Lipid Regulating Agents
Lipoproteins, HDL
Liver
Models, Biological
Molecular Targeted Therapy