HDL in the 21st Century: A Multifunctional Roadmap for Future HDL Research

Abstract

Low high-density lipoprotein cholesterol (HDL-C) characterizes an atherogenic dyslipidemia that reflects adverse lifestyle choices, impaired metabolism, and increased cardiovascular risk. Low HDL-C is also associated with increased risk of inflammatory disorders, malignancy, diabetes, and other diseases. This epidemiologic evidence has not translated to raising HDL-C as a viable therapeutic target, partly because HDL-C does not reflect high-density lipoprotein (HDL) function. Mendelian randomization analyses that have found no evidence of a causal relationship between HDL-C levels and cardiovascular risk have decreased interest in increasing HDL-C levels as a therapeutic target. HDLs comprise distinct subpopulations of particles of varying size, charge, and composition that have several dynamic and context-dependent functions, especially with respect to acute and chronic inflammatory states. These functions include reverse cholesterol transport, inhibition of inflammation and oxidation, and antidiabetic properties. HDLs can be anti-inflammatory (which may protect against atherosclerosis and diabetes) and proinflammatory (which may help clear pathogens in sepsis). The molecular regulation of HDLs is complex, as evidenced by their association with multiple proteins, as well as bioactive lipids and noncoding RNAs. Clinical investigations of HDL biomarkers (HDL-C, HDL particle number, and apolipoprotein A through I) have revealed nonlinear relationships with cardiovascular outcomes, differential relationships by sex and ethnicity, and differential patterns with coronary versus noncoronary events. Novel HDL markers may also have relevance for heart failure, cancer, and diabetes. HDL function markers (namely, cholesterol efflux capacity) are associated with coronary disease, but they remain research tools. Therapeutics that manipulate aspects of HDL metabolism remain the holy grail. None has proven to be successful, but most have targeted HDL-C, not metrics of HDL function. Future therapeutic strategies should focus on optimizing HDL function in the right patients at the optimal time in their disease course. We provide a framework to help the research and clinical communities, as well as funding agencies and stakeholders, obtain insights into current thinking on these topics, and what we predict will be an exciting future for research and development on HDLs.

High Density Lipoproteins: Is There a Comeback as a Therapeutic Target?

“…By contrast to the disease causing cholesterol in LDL (Borén et al 2020), the cholesterol in HDL (that is HDL-C) neither exerts nor reflects any of the potentially anti-atherogenic activities of HDL. HDL-C is only a non-functional surrogate marker for estimating the HDL pool size without deciphering the heterogeneous composition and, hence, functionality of HDL (Rohatgi et al 2021;von Eckardstein 2013, 2016). Differences in the molar content of apoA-I, phosphatidylcholines, cholesterol, and cholesteryl ester cause differences of HDL subclasses in shape, size, and charge.…”

“…Differences in the molar content of apoA-I, phosphatidylcholines, cholesterol, and cholesteryl ester cause differences of HDL subclasses in shape, size, and charge. HDL particles carry hundreds of different quantitatively minor proteins and lipid species many of which are not just passive cargo (like cholesterol) but biologically active and susceptible to quantitative and qualitative modifications by diseases or interventions (Rohatgi et al 2021, Annema and von Eckardstein 2013. These functionally active components hence have a much bigger chance than HDL-C to serve as a causal biomarker that can be exploited towards the development, targeting, and monitoring of therapies.…”

“…HDL particles exert a broad spectrum of biological activities many of which are considered as anti-atherogenic, for example mediation of cholesterol efflux from macrophage foam cells and reverse transport of cholesterol to the liver, promotion of endothelial integrity and function, inhibition of inflammation by suppression of myelopoiesis and transmigration of leukocytes through the endothelium as well as macrophage activation, inhibition of lipid oxidation as well as inactivation of oxidized lipids (Fig. 1) (Von Eckardstein and Kardassis 2015; Robert et al 2021;Rohatgi et al 2021). Furthermore, atherosclerosis could be decreased or even reverted in several animal models by transgenic over-expression or exogenous application of apolipoprotein (apoA-I), i.e.…”

The Capacity of APOB-Depleted Plasma in Inducing ATP-Binding Cassette A1/G1-Mediated Macrophage Cholesterol Efflux—But Not Gut Microbial-Derived Metabolites—Is Independently Associated with Mortality in Patients with ST-Segment Elevation Myocardial Infarction

“…The ability of high-density lipoprotein (HDL) particles to stimulate cholesterol efflux from macrophage foam cells, the first step of reverse cholesterol transport (RCT), is one major recognized HDL cardioprotective function [1]. Macrophage cholesterol efflux to HDL occurs via different mechanisms, termed simple aqueous diffusion, facilitated by scavenger receptor class B type I (SR-BI) and active transport induced by the transmembrane protein ATP-binding cassette transporter ABCA1 and ABCG1 (ABCA1/G1)-mediated pathways.…”

A genetic sum score of effect alleles associated with serum lipid concentrations interacts with educational attainment

“…Elevated serum concentration of low-density lipoprotein cholesterol (LDL-C) is an important causal risk factor for cardiovascular disease (CVD) 1 – 3 and has now largely replaced total cholesterol (TC) as the primary treatment target for dyslipidemia 1 . Reduced serum concentration of high-density lipoprotein cholesterol (HDL-C) is independently associated with CVD 4 , 5 , in genetic studies however, HDL-C has not been causally associated with CVD 3 . Serum lipid concentrations (in the following named as lipids) are complex human traits that are influenced by both genetic and lifestyle factors 6 .…”