Small HDL promotes cholesterol efflux by the ABCA1 pathway in macrophages: implications for therapies targeted to HDL.

Abstract

Clinical and epidemiological studies show a robust, inverse association of high-density lipoprotein (HDL) levels with cardiovascular disease (CVD) risk.1 Moreover, genetically engineered mice provide compelling evidence that HDL is atheroprotective in hypercholesterolemic animal models. These observations have triggered intense interest in targeting HDL for therapeutic intervention. Article, see p 1133 Most clinical studies have used HDL-cholesterol (HDL-C) as the metric for quantifying HDL’s cardioprotective effects. However, recent evidence has raised doubts about elevating HDL-C being therapeutic.1 For example, genetic variations that associate with altered HDL-C levels do not strongly associate with altered CVD risk. Also, prospective clinical trials of niacin and cholesteryl ester transfer protein inhibitors (2 drugs that elevate HDL-C levels by different mechanisms) failed to reduce cardiac events in statin-treated subjects with established CVD.1 Moreover, when mice lack certain proteins involved in HDL metabolism—such as SR-B1, the liver receptor for HDL—both HDL-C levels and atherosclerosis increase dramatically.2 Thus, quantifying HDL-C does not necessarily assess HDL’s proposed ability to lower CVD risk. Many lines of evidence indicate that one of HDL’s cardioprotective tasks is to mobilize excess cholesterol from artery wall macrophages.1 For example, mouse studies demonstrate that increased hepatic expression of apolipoprotein A-I, the major HDL protein, increases cholesterol export from macrophages and retards atherosclerosis. Two pathways for sterol export involve the membrane-associated ATP-binding cassette transporters (ABC) ABCA1 and ABCG1, which are highly induced when macrophages accumulate excess cholesterol.1 Thus, atherosclerosis increases markedly in hypercholesterolemic mice when myeloid cells are deficient in ABCA1. Also, humans with ABCA1 deficiency had Tangier’s disease and accumulate macrophages laden with cholesterol in many tissues.3 These observations support the proposal that HDL, ABCA1, and sterol efflux from cells are important regulators of sterol balance in human macrophages. The relevance of sterol efflux from macrophages in humans …