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Plasma lipoproteins can be separated by ultracentrifugation based on their physical properties, without direct reference to their composition, with ‘high-density’ lipoproteins (HDL) comprising those with density greater than 1.063 g/ml. HDL lipoprotein particles should be explicitly distinguished from HDL-cholesterol, which is but one of the constituents of HDL. Apolipoprotein A-I is the major structural protein of HDL and comprises 70% of total HDL protein. In addition, there is a large number of protein constituents, the functions of which broadly span lipid transport, inflammation, immune function, hormone binding, haemostasis and antioxidant functions.1 Our appreciation of the context-specific roles of these proteins remains rudimentary, and tools to quantify their putative contributions still more so. On the other hand, measurement of HDL-cholesterol is relatively straightforward and has been undertaken widely.
HDL has come to be regarded as atheroprotective, based on three lines of evidence: (1) the inverse relationship between cardiovascular event rates and HDL-cholesterol that is seen in epidemiological studies; (2) animal data showing that the administration of apolipoprotein AI and/or HDL particles reduce atherosclerosis and (favourably remodel atherosclerotic plaques); and (3) a small number of clinical trials suggesting that some drugs that elevate HDL-cholesterol also reduce cardiovascular events or result in plaque regression, assessed by ultrasound or MRI. These observations have raised the possibility that interventions that increase HDL-cholesterol might reduce cardiovascular risk. However, several recent findings have challenged this notion. First, alterations of HDL-cholesterol that are associated with naturally occurring, genetic polymorphisms allow the effects of changes in HDL-cholesterol due to Mendelian randomisation to be mapped to cardiovascular risk. Alterations in HDL-cholesterol by these means do not track with predicted cardiovascular risk. Secondly, niacin (nicotinic acid) is the most efficacious of clinically available drugs to elevate HDL-cholesterol. The AIM–HIGH trial of niacin in patients with low HDL-cholesterol was abandoned due to …
Contributors Design by RPC. Literature review, drafts and revisions by RPC and NR. Final critical review and amendments by RPC.
Funding RPC and NR acknowledge the support of the BHF Centre of Research Excellence, Oxford. RPC is a Wellcome Trust senior research fellow in clinical science. Our laboratory is supported by the Oxford Comprehensive Biomedical Research Centre, NIHR funding scheme.
Competing interests None.
Provenance and peer review Commissioned; internally peer reviewed.
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