High-density lipoprotein revisited: biological functions and clinical relevance

Abstract

Previous interest in high-density lipoproteins (HDLs) focused on their possible protective role in atherosclerotic cardiovascular disease (ASCVD). Evidence from genetic studies and randomized trials, however, questioned that the inverse association of HDL-cholesterol (HDL-C) is causal. This review aims to provide an update on the role of HDL in health and disease, also beyond ASCVD. Through evolution from invertebrates, HDLs are the principal lipoproteins, while apolipoprotein B-containing lipoproteins first developed in vertebrates. HDLs transport cholesterol and other lipids between different cells like a reusable ferry, but serve many other functions including communication with cells and the inactivation of biohazards like bacterial lipopolysaccharides. These functions are exerted by entire HDL particles or distinct proteins or lipids carried by HDL rather than by its cholesterol cargo measured as HDL-C. Neither does HDL-C measurement reflect the efficiency of reverse cholesterol transport. Recent studies indicate that functional measures of HDL, notably cholesterol efflux capacity, numbers of HDL particles, or distinct HDL proteins are better predictors of ASCVD events than HDL-C. Low HDL-C levels are related observationally, but also genetically, to increased risks of infectious diseases, death during sepsis, diabetes mellitus, and chronic kidney disease. Additional, but only observational, data indicate associations of low HDL-C with various autoimmune diseases, and cancers, as well as all-cause mortality. Conversely, extremely high HDL-C levels are associated with an increased risk of age-related macular degeneration (also genetically), infectious disease, and all-cause mortality. HDL encompasses dynamic multimolecular and multifunctional lipoproteins that likely emerged during evolution to serve several physiological roles and prevent or heal pathologies beyond ASCVD. For any clinical exploitation of HDL, the indirect marker HDL-C must be replaced by direct biomarkers reflecting the causal role of HDL in the respective disease.

Keywords: Age-related macular degeneration; Autoimmune disease; Cancer; Cholesterol efflux; Evolution; Infectious disease; Remnants; Triglycerides.

Graphical Abstract

The great complexity of HDL. High-density lipoprotein (HDL) particles carry a large number of proteins and lipids, which contribute to define their compositional and functional complexity. HDLs exert multiple protective activities, essentially by three major mechanisms. HDLs, however, can lose their protective functions and even gain adverse functions in chronic diseases or during infections. U-shaped relationships between HDL-cholesterol (HDL-C) levels and several conditions have been reported, being both low and extremely high HDL-C levels associated with an increased risk of several pathologies and mortality. LCAT, lecithin:cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; PONI, paraoxonase 1; S1P, sphingosine-1-phosphate; ASCVD, atherosclerotic cardiovascular disease; LDL, low-density lipoprotein; SAA, serum amyloid A; OxPL, oxidized phospholipids

Figure 1

High and low abundant lipids and proteins in high-density lipoprotein particles. Apo, apolipoprotein; LCAT, lecithin:cholesterol acyltransferase; CETP, cholesteryl ester transfer protein; PONI, paraoxonase 1; S1P, sphingosine-1-phosphate.

Figure 2

Cholesterol transfers between high-density lipoprotein, very-low-density lipoprotein, low-density lipoprotein, and cells. ABCA1, ATP-binding cassette transporter A1; ABCG1, ATP-binding cassette transporter G1; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FC, free cholesterol, unesterified cholesterol; HDL, high-density lipoprotein; HL, hepatic lipase; LCAT, lecithin:cholesterol acyltransferase; LDL, low-density lipoprotein; LPL, lipoprotein lipase; PLTP, phospholipid transfer protein; SR-B1, scavenger receptor B1.

Figure 3

Structure–function relationships of high-density lipoprotein in health and disease. RNA, ribonucleic acid.

Figure 4

Lipoprotein-cholesterol as a function of increasing levels of non-fasting triglycerides. Based on 60 000 individuals from the Copenhagen General Population Study. CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; TG, triglycerides. Adapted from Chapman et al.

Figure 5

High-density lipoprotein levels on a continuous scale and risk of all-cause mortality in men and women from the Copenhagen General Population Study. Adapted from Madsen et al.

Figure 6

High-density lipoprotein levels on a continuous scale and risk of infectious disease, autoimmune disease, and cancer in individuals from the Copenhagen General Population Study. Adapted from Madsen et al. and Pedersen et al.

Figure 7

Estimated benefit and harm due to genetically lower non-high-density lipoprotein-cholesterol and genetically higher high-density lipoprotein-cholesterol due to inhibition of cholesteryl ester transfer protein. Based on individuals in the Copenhagen General Population Study. Lower non-high-density lipoprotein-cholesterol by 0.44 mmol/L (17 mg/dL) and higher high-density lipoprotein-cholesterol by 1.12 mmol/L (43 mg/dL) correspond to the changes observed through anacetrapib treatment compared with placebo in the REVEAL trial. AMD, age-related macular degeneration; HDL, high-density lipoprotein; Δ=difference. Adapted from Nordestgaard et al.

Figure 8

Examples of relative mass distribution of different lipoprotein fractions in different invertebrate and vertebrate species. HDL, high-density lipoprotein; LDL, low-density lipoprotein; VLDL, very-low-density lipoprotein. Values adapted from Chapman and Van der Horst and Rodenburg.