Enhanced ability of HDL to promote cholesterol efflux in CETP-deficient subjects

Genetic deficiency or inhibition of cholesteryl ester transfer protein (CETP) leads to a marked increase in high-density lipoprotein (HDL) cholesterol levels, in particular increasing the level of large HDL-2 particles. There has been concern that these HDL-2 particles associated with CETP deficiency are functionally defective (i.e. have impaired function). However, recent evidence1 indicates that this is not the case. Instead, these particles have an enhanced ability to promote cholesterol efflux from macrophages, suggesting that CETP inhibition may have potential as a therapy for atherosclerotic cardiovascular disease.

CETP is a plasma protein that promotes the redistribution of cholesteryl esters and triglyceride between plasma lipoproteins. The net effect of its action is transfer of cholesteryl esters from HDL to triglyceride-rich lipoproteins in exchange for triglyceride that is transferred from triglyceride-rich lipoprotein to HDL. Inhibition of CETP leads to substantial increases in HDL cholesterol.

The aim of this study was to investigate the ability of HDL from subjects who were deficient in CETP to promote cholesterol efflux from macrophages, and to investigate the role of various factors in this process. The researchers used mouse peritoneal macrophages treated with the liver X receptor activator T0901317 (which stimulates cholesterol efflux to HDL) to investigate the function of HDL-2 particles.

Cholesterol efflux of HDL-2 particles from CETP deficient subjects was 2 to 3-fold greater compared with HDL-2 particles from control subjects. The researchers showed that this effect was mainly due to an increase in cholesteryl ester formation mediated by lecithin:cholesterol acyltransferase (LCAT). LCAT acts mainly on cholesterol in HDL, and is responsible for generating virtually all cholesteryl esters in the plasma. This enzyme plays a key role in the metabolism and modelling of HDL.

The researchers also showed that ATP-binding cassette G1 (ABCG1), a cell membrane transporter that promotes transfer of cholesterol from cells to large HDL in the extracellular space, has an essential role in the ability of HDL-2 particles from CETP deficient subjects to stimulate increased cholesterol efflux.

References

1. Matsuura F, Wang N, Chen W et al. HDL from CETP-deficient subjects shows enhanced ability to promote cholesterol efflux from macrophages in an apoE- and ABCG1-dependent pathway. J Clin Invest 2006;116:1435-42.

Commentary

The development of new agents that inhibit activity of CETP and dramatically increase HDL levels has generated enormous interest. While increasing HDL levels should reduce the risk of cardiovascular disease, the possibility that it may not be beneficial must also be considered. There are two underlying reasons for a possible lack of benefit: Firstly, CETP inhibition increases the number of large HDL particles at the expense of the small HDL particles that accept cholesterol that is exported from cells by ABCA1. Secondly, inhibition of CETP prevents transfer of cholesteryl esters from HDL to LDL, and the subsequent removal of these cholesteryl esters from the circulation via the LDL receptor. The recent discovery that cholesterol can be exported from cells to large HDL by ABCG1 suggested that the first of these concerns may be unfounded. This report by Matsuura and colleagues shows for the first time that large HDL from individuals who are naturally deficient in CETP are excellent acceptors of the cholesterol that is exported from lipid-laden foam cells by ABCG1.

However, recent interim findings from the ILLUMINATE trial with the CETP inhibitor torcetrapib, which showed an excess of deaths among patients treated with torcetrapib plus atorvastatin versus atorvastatin alone and led to early termination of development of this compound, should be borne in mind. Ongoing analyses are investigating the reason for this unexpected finding. In the meantime, we await further data relating to the effects of CETP inhibition.