Endocrine Abstracts

With the success of statins in lowering LDL cholesterol and reducing cardiovascular disease (CVD) event rate, interest is shifting towards HDL cholesterol (HDL-C) as a potential target for therapeutic intervention.

High HDL-C is associated with low CVD event rate. Reverse cholesterol transport may contribute to this association, and describes transfer of cholesterol on HDL particles from peripheral tissues to the liver. The transport process involves: ATP-binding cassette transporter A1 mediated efflux of intracellular unesterified cholesterol to discoidal lipid-poor HDL particles; cholesterol esterification by lecithin:cholesterol acyltransferase; packaging of cholesterol ester into the particle core which becomes more spherical; and delivery of cholesterol ester to the liver for excretion in bile. Hepatic cholesterol delivery can be direct, mediated by scavenger-receptor B1 which selectively takes up the cholesterol from HDL. It can also be indirect, by cholesterol ester transfer protein (CETP) mediated exchange of the cholesterol ester for triglyceride on apolipoprotein B-containing lipoproteins, which are themselves then taken up by the liver. However, increasing flux through the pathway can lower measured HDL-C, so that the relationships between cholesterol flux, HDL-C, and CVD, are unclear.

The paradox of high CVD and high HDL-C in Type 1 diabetes is poorly understood. Type 2 diabetes is associated with high CVD and low HDL-C. The low HDL-C is thought to result from hypertriglyceridaemia. Hypertriglyceridaemia drives the CETP mediated exchange of cholesterol ester for triglyceride. HDL becomes triglyceride enriched, its triglyceride is hydrolised by hepatic lipase to produce smaller, denser HDL particles that are better substrates for catabolic pathways, and both HDL particle number and HDL-C decrease.

Variations in triglyceride account for only 25% of the variation in HDL-C, so that there are likely to be other mechanisms for low HDL-C in Type 2 diabetes. Mechanisms involving the proximal steps of reverse cholesterol transport require further elucidation.