Novel HDL-directed pharmacotherapeutic strategies

Abstract

The burden of atherothrombotic cardiovascular disease remains high despite currently available optimum medical therapy. To address this substantial residual risk, the development of novel therapies that attempt to harness the atheroprotective functions of HDL is a major goal. These functions include the critical role of HDL in reverse cholesterol transport, and its anti-inflammatory, antithrombotic, and antioxidant activities. Discoveries in the past decade have shed light on the complex metabolic and antiatherosclerotic pathways of HDL. These insights have fueled the development of HDL-targeted drugs, which can be classified among four different therapeutic approaches: directly augmenting apolipoprotein A-I (apo A-I) levels, such as with apo A-I infusions and upregulators of endogenous apo A-I production; indirectly augmenting apo A-I and HDL-cholesterol levels, such as through inhibition of cholesteryl ester transfer protein or endothelial lipase, or through activation of the high-affinity niacin receptor GPR109A; mimicking the functionality of apo A-I with apo A-I mimetic peptides; and enhancing steps in the reverse cholesterol transport pathway, such as via activation of the liver X receptor or of lecithin-cholesterol acyltransferase.

Figure 1

HDL metabolism and targets of therapeutic intervention. Synthesized by the liver and the intestine, apo A-I acquires phospholipid to form nascent preβ-HDL. ABCA1 initiates the first step of reverse cholesterol transport, facilitating the efflux of free cholesterol from peripheral cells to nascent preβ-HDL. LCAT esterifies the cholesterol molecules to form cholesteryl esters, which migrate to the core of the HDL particle, resulting in formation of α-HDL. These mature HDL particles can acquire additional lipid via efflux mediated by ABCG1 and SR-BI. CETP mediates exchange of cholesteryl esters for triglycerides with VLDL or LDL, effecting depletion in cholesteryl esters and enrichment in triglycerides of HDL. The resulting HDL3 particles can be either taken up by the liver via SR-BI holoparticle uptake or modified by hepatic lipase and endothelial lipase. Metabolism by the latter releases lipid-poor apo A-I, which can be filtered by the glomeruli and degraded by cubilin/megalin in the proximal renal tubule. Targets of HDL-directed therapeutic interventions are indicated by red arrows and lines. Abbreviations: ABC, ATP-binding cassette transporter; Apo A-I, apolipoprotein A-I; CETP, cholesteryl ester transfer protein; CD36 and LIMPII analogous-1; LCAT, lecithin–cholesterol acyltransferase; LDL-R, LDL receptor; SR-BI, scavenger receptor class B type I.