HDL cholesterol: reappraisal of its clinical relevance

Abstract

Background: While several lines of evidence prove that elevated concentrations of low-density lipoproteins (LDL) causally contribute to the development of atherosclerosis and its clinical consequences, high-density lipoproteins are still widely believed to exert atheroprotective effects. Hence, HDL cholesterol (HDL-C) is in general still considered as "good cholesterol". Recent research, however, suggests that this might not always be the case and that a fundamental reassessment of the clinical significance of HDL-C is warranted.

Method: This review article is based on a selective literature review.

Results: In individuals without a history of cardiovascular events, low concentrations of HDL-C are inversely associated with the risk of future cardiovascular events. This relationship may, however, not apply to patients with metabolic disorders or manifest cardiovascular disease. The classical function of HDL is to mobilise cholesterol from extrahepatic tissues for delivery to the liver for excretion. These roles in cholesterol metabolism as well as many other biological functions of HDL particles are dependent on the number as well as protein and lipid composition of HDL particles. They are poorly reflected by the HDL-C concentration. HDL can even exert negative vascular effects, if its composition is pathologically altered. High serum HDL-C is therefore no longer regarded protective. In line with this, recent pharmacological approaches to raise HDL-C concentration have not been able to show reductions of cardiovascular outcomes.

Conclusion: In contrast to LDL cholesterol (LDL-C), HDL-C correlates with cardiovascular risk only in healthy individuals. The calculation of the ratio of LDL-C to HDL-C is not useful for all patients. Low HDL-C should prompt examination of additional metabolic and inflammatory pathologies. An increase in HDL-C through lifestyle change (smoking cessation, physical exercise) has positive effects and is recommended. However, HDL-C is currently not a valid target for drug therapy.

Keywords: Cholesterol; HDL; Review.

Fig. 1

Epidemiological association of low HDL-C serum concentrations with CHD risk. Data from the Emerging Risk Factors Collaboration [3]. With permission of Springer [7]

Fig. 2

Role of HDL in lipoprotein metabolism. Apo A1, the main protein in HDL, is formed in the liver and the small intestine and secreted as lipid-free pre-ß-HDL. Pre-b-HDL can also come from chylomicron metabolism, or from the interconversion of HDL itself. Their interaction with ATP-binding cassette transporter A1 (ABCA1) leads to the efflux of phosphatidylcholine (PC) and free cholesterol (FC), and thus to the formation of disc-shaped HDL. Esterification of the free cholesterol by lecithin–cholesterol acyltransferase (LCAT) leads to the formation of mature spherical HDL. The lipid-rich discoidal and spherical HDL enable passive diffusion out of cells, which is facilitated by ATP-binding cassette transporter G1 (ABCG1), scavenger receptor class B type I (SR-B1) and by cholesterol esterification mediated by LCAT. Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters (CE), triglycerides and phospholipids (PL) between HDL, LDL and VLDL. It thereby contributes to the formation of LDL, which is taken up through LDL receptors (LDLR) in hepatocytes. Phospholipid transfer protein (PLTP) belongs to the same protein family as CETP. Its function is to transport phospholipids between HDL and VLDL, and between various HDL. Mediated by SR-BI, HDL can deliver cholesteryl ester (and free cholesterol) to hepatocytes, steroid-producing cells and adipocytes. With permission of Springer [7]

Fig. 3

Aetiologies of low HDL cholesterol. With permission of Springer [7]

Fig. 4

Cellular cholesterol efflux and cardiovascular mortality. Kaplan–Meier curves and hazard ratios by quartiles of cholesterol efflux capacity. Model 1: adjusted for age and gender; Model 2: also adjusted for use of lipid-lowering drugs, CHD (none, stable, unstable CHD, NSTEMI, STEMI), body mass index, hypertension, smoking, LDL-C/HDL-C ratio, triglycerides, metabolic syndrome/type 2 diabetes mellitus [26]. With permission of Springer [7]