High-density lipoproteins. Part 2. Impact of disease states on functionality

Abstract

In contrast to low-density lipoproteins which are atherogenic, high-density lipoproteins (HDL) have been conceptualized as beneficial modulators of adverse pathophysiological phenomena along arterial walls. The HDLs are characterized by highly complex and varied molecular cargoes that include apoproteins, enzymes, microRNAs, bioactive lipids and phospholipids, components of complement, and immune factors, among others. These cargo components determine its functionality. Despite the findings of Mendelian inheritance studies which suggest that HDL is not causal in the pathway for atherogenesis, experiments with HDLs show that it can drive reverse cholesterol transport and antagonize inflammation, oxidation, thrombosis, platelet aggregation, endothelial progenitor cell mobilization, potentiate immunity, foster communication between different cell and tissue types, and function as a crucial apoprotein donor amongst the various lipoproteins. These functions are understandably viewed as beneficial and antagonize pathophysiology. Secondary to the complexity of its proteome and lipidome, HDL functionality is profoundly responsive to the metabolic and genetic backgrounds of individuals. Even its size and lipidation status can influence its functionality. As part of the acute phase response, critical antioxidative moieties can be replaced by such acute phase reactants as serum amyloid A and pro-oxidative enzymes. The functionality of HDL is influenced by chronic kidney disease, coronary artery disease, acute myocardial infarction, obesity, insulin resistance, metabolic syndrome, diabetes mellitus, and cancer. Herein we describe many of the alterations in HDL constitution and the resulting changes in functional capacity that can be observed. A unifying theme characterizing these disease states is that they all heighten systemic inflammatory tone and potentiate a pro-oxidative state. These changes clearly associate with profound changes in the functionality and behavior of HDL particles. We are only beginning to comprehend the extraordinary complexity and range of biochemical functions, both beneficial and injurious, that this lipoprotein can regulate. Hence it was extremely premature to think that simply raising HDL cholesterol in serum would beneficially influence cardiovascular morbidity and mortality. We have a long way to go before we develop a more comprehensive and potentially therapeutically relevant understanding of how to better harness its potential for antagonizing disease and block its ability to participate in and adversely influence the course of disease.

Keywords: Atherosclerosis; Epidemiology; High-density lipoprotein; Inflammation; Oxidation; Reverse cholesterol transport; Thrombosis.

Graphical abstract

Figure 1

HDL Metabolism. ApoA1 is secreted from hepatocytes and can be lipidated by hepatic ABCA1. ApoA1 is also produced and lipidated by the small intestine and adipocytes. Macrophages and adipocytes express ABCA1 and ABCG1 which are used to lipidate nascent discoidal HDL and spherical HDL, respectively. These cells also express S-BI, which can mediate bidirectional flux of cholesterol in and out of the cytosol. LCAT esterifies cholesterol on the surface of HDL particles; cholesterol esters follow a concentration gradient into the particle’s hydrophobic core, making the particle more spherical and larger. Smaller and larger HDL particles are generally designated as HDL₃ and HDL₂, respectively. During direct reverse cholesterol transport, HDL particles transport cholesterol esters from the periphery back to the liver for disposal. En route, HDL can undergo modification via the activity of a variety of enzymes. EL and HL both convert larger HDL particles into smaller ones; EL hydrolyzes phospholipids, while HL hydrolyzes both phospholipids and triglycerides. As lipolysis progresses, lipid-poor ApoA1 can bind to megalin and cubulin and be eliminated in the renal ultrafiltrate. HDL can transfer apoCII and apoE to chylomicron remnants and facilitate their clearance from the circulation via the LDL-R and LRP on the surface of hepatocytes. HDL₂ functions as an important reservoir and transfer agent of cholesterol ester for steroidogenic tissues. CETP participates in indirect RCT; it catalyzes a molar 1:1 exchange of cholesterol ester out of HDL for triglycerides in apoB-containing lipoproteins. In this scenario, the cholesterol is delivered back to the liver via LDL-R and LRP. HDL₂ delivers cholesterol ester to hepatocytes via two cell surface receptors: SR-BI which drives HDL delipidation and release of the particle back into the circulation and ecto-F1 ATPase which promotes holoparticle uptake and clearance of the HDL particle.

Figure 2

Cardioprotective Mechanisms of Action by HDL Particles. In addition to regulating direct RCT, HDL particles appear to participate in a variety of effects beneficial to endothelium and antagonistic to atherogenesis. HDL promotes the mobilization and extracellular translocation of cholesterol from macrophages via ABCA1 and ABCG1. HDL particles carry a variety of anti-oxidative enzymes such as PON-1 and glutathione peroxidase as well as apoproteins A1 and A2 which are also anti-oxidative. This may reduce the oxidation LDL particles in the subendothelial space. The HDLs also carry microRNAs (e.g., miR-223 and miR-486) which allow different cell types and tissues to communicate with one another. HDL is an important vehicle for transporting S1P in plasma. The S1P binds to S1P3 receptors on endothelial cells to inhibit apoptosis, potentiate nitric oxide production and vasodilatation, down regulate adhesion molecule expression (e.g., ICAM-1, VCAM-1) and inhibit inflammation. HDL particles can also inhibit platelet activation and aggregation through a variety of mechanisms.

Figure 3

Dysfunctional HDL and Loss of Cardioprotective Properties. The consensus HDL proteome is comprised of hundreds of molecular species. HDL is an important carrier vehicle for apoproteins, enzymes, globulins, and immune factors, among others. The HDL proteome is highly responsive to the internal milieu and can change in response to pathophysiological conditions. This can render the HDL particle pro-oxidative, pro-inflammatory, and prothrombotic. In the setting of diabetes HDL can become heavily glycated, impairing its functionality. During the acute phase response critical beneficial enzymes and proteins may become displaced by serum amyloid A, fibrinogen, haptoglobin, and other components of the acute phase response. Myeloperoxidase can bind to HDL and render it pro-oxidative via oxidation and carbamylation of the proteome and a variety of lipids. In chronic kidney disease, HDLs can become enriched with symmetric dimethylarginine, which can antagonize the effects of SIP on endothelial cells, leading to increased adhesion molecule expression, apoptosis, and inflammation, and decreased vasodilatation due to impaired nitric oxide production. ApoA1 function can become compromised rendering it less anti-oxidative and less capable of binding to ABCA1 and ABCG1 to drive RCT.