Effects of Lipid-Lowering Drugs on High Density Lipoprotein Structure and Metabolism

Abstract

The inverse relationship between plasma high density lipoproteins (HDL) and cardiovascular risk, though amply documented in the 1960s (Gofman et al. 1966), was not widely appreciated until its re-emphasis in the publication of Miller and Miller (1975). Even now, despite the weight of evidence supporting the concept, our understanding of the mechanism which underlies it remains rudimentary. The most popular view (Miller 1984) endows the lipoprotein with the capacity to accept cholesterol from parenchymal cells, possibly following its interaction with a membrane receptor which recognises the major apolipoprotein A component of the particle. Esterification of the assimilated sterol by lecithin:cholesterol acyltransferase leads to its entrapment within the hydrophobic core of the particle which expands and limits continued cholesterol uptake. At this point it is envisaged that further cycles of sterol capture depend upon transfer of the core ester into less dense lipoproteins. These apolipoprotein B-containing very low and low density lipoproteins (VLDL and LDL) are probably responsible for the ultimate delivery of sterol to the liver, so making centripetal cholesterol transport dependent on the integrated activities of all major plasma lipoprotein fractions. Thus, it is not surprising that most prescribed hypo-lipidaemic drugs, which were originally designed to lower plasma VLDL and LDL, should also have an impact on HDL metabolism.