Molecular regulation of HDL metabolism and function: implications for novel therapies

Abstract

HDL metabolism represents a major target for the development of therapies intended to reduce the risk of atherosclerotic cardiovascular disease. HDL metabolism is complex and involves dissociation of HDL apolipoprotein and HDL cholesterol metabolism. Advances in our understanding of the molecular regulation of HDL metabolism, macrophage cholesterol efflux, and HDL function will lead to a variety of novel therapeutics.

Figure 1. HDL biosynthesis.

Enterocytes and hepatocytes synthesize apoA-I, which is secreted in a lipid-poor form and then immediately recruits additional PLs and free cholesterol (FC) via the ABCA1 pathway, forming nascent HDL. Nascent HDL acquires more lipid from other peripheral tissues and from lipoproteins, and LCAT generates CE, forming mature HDL. The liver also synthesizes apoA-II, which results in a subclass of HDL containing both apoA-I and apoA-II.

Figure 2. Pathways of HDL cholesterol uptake by the liver.

HDL-CE and HDL free cholesterol can be directly and selectively taken up by the liver via SR-BI. Alternatively, HDL-CE can be transferred to apoB-containing lipoproteins by CETP and then taken up by liver via the LDLR. In the hepatocyte, CE is hydrolyzed to free cholesterol, which is either excreted directly into the bile or converted to bile acid (BA) and excreted into the bile.

Figure 3. Pathways of apoA-I catabolism.

Lipid-poor apoA-I can be filtered through the renal glomerulus and be degraded by the renal tubular cell via the cubulin-megalin pathway. Lipid-poor apoA-I is generated by the action of lipases such as HL and EL on mature HDL, and the action of these lipases is enhanced by the CETP-mediated transfer of TG into HDL. Mature HDL can also be catabolized by the hepatocyte through binding of HDL-apoE to hepatic receptors or through a poorly characterized mechanism of direct interaction with the hepatocyte. AMN, amnionless.

Figure 4. Pathways of cholesterol efflux from macrophages.

Macrophages have several pathways for efflux of cholesterol. They efflux free cholesterol to lipid-poor apoA-I via the ABCA1 pathway and to mature HDL via the ABCG1 pathway. Both ABCA1 and ABCG1 are regulated by the nuclear receptor LXR, which is activated by binding of oxysterols, derived from free cholesterol. SR-BI also has the capacity to efflux free cholesterol to mature HDL.