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.

Keywords: atherosclerosis; biomarkers; inflammation; lipoproteins; lipoproteins, HDL.

Figure 1 –

Anti-and pro-inflammatory effects of HDL in Macrophages A. Anti-inflammatory effects. 1. HDL induces cholesterol efflux mediated by the cholesterol transporters ABCA1 and ABCG1, leading to a decreased TLR4 surface expression and decreased downstream MyD88 and TRIF signaling, suppressing the NF-κB and type I IFN response, respectively. 2. HDL stimulates the translocation of TRAM from the plasma membrane to intracellular compartments, reducing its availability for TRIF signaling and diminishing type I IFN production. 3. HDL induces Atf3 expression as such suppressing TLR9 or TLR1/2 induced inflammatory gene expression downstream of NF-κB. Dashed arrow indicates that the exact mechanism is unknown. Yellow dots indicate free cholesterol and in the case of HDL, particle free cholesterol enrichment because of cholesterol efflux. B. Pro-inflammatory effects. 4. ApoA-1 binds to TLR2 and TLR4, enhancing MyD88 signaling and NF-κB activation, and TRIF signaling (although not shown). 5. HDL induces plasma membrane cholesterol depletion, augmenting PKC signaling and downstream NF-κB activation induced by a TLR ligand. 6. HDL induces excessive cholesterol depletion, leading to ER membrane perturbation and enhanced IRE1a/ASK1/p38 MAPK signaling, which augments NF-κB activation in the presence of LPS (shown as TLR4 activation). Dashed arrows (in A and B) indicate that the exact mechanism is unknown.

Figure 2:

Concentration ranges of high-density lipoprotein (HDL) particles as well as the different proteins and lipids found in HDL. The width of the triangle’s baseline axis reflects the concentrations of HDL particles and components which range from more than 1 mmol/L (i.e. 10⁻³ mol/L for cholesterol) to the submicromolar range (i.e. 10⁻⁷ or even 10⁻⁸ mol/L for lipids such as sphingosine-1-phosphates and oxysterols or proteins such as apoL1 or phospholipid transfer protein (PLTP). The numbers at the left diagonal axis of the triangle shows the abundance of HDL subclasses or components relative to an average concentration of HDL particles of 20 μmol/L, which is highlighted with the bold line crossing the triangle at 10⁰ = 1. The curly brackets on the right side of the triangle reflect the measuring ranges of analytical methods used for the characterization of HDL. HDL subclasses are denoted by purple font, lipids by red font, and proteins by blue font. MicroRNAs are not presented but their concentration of 10000 copies per μg HDL protein implies a relative abundance of about one molecule per 10⁷ HDL particles. Abbreviations: Apo, apolipoprotein; CETP, cholesteryl ester transfer protein; LCAT, lecithin:cholesterol acyltransferase; PLTP, phospholipid transfer protein.

Figure 3.

A Conceptual Framework for Investigating the Translational and Clinical Impact of HDLs. HDLs comprise multiple subpopulations with diverse functions that are context dependent. Use of -omics approaches in diverse human cohorts with and without disease will help identify these context-dependent functions of specific HDLs to improve risk prediction and therapeutic strategies for both cardiovascular and non-cardiovascular diseases.