High-Density Lipoprotein in Lupus: Disease Biomarkers and Potential Therapeutic Strategy

Abstract

Systemic lupus erythematosus (SLE) patients exhibit accelerated development of atherosclerosis and increased incidents of cardiovascular disease (CVD) that cannot be explained by traditional risk factors alone. Accumulating evidence suggests that reduced levels of high-density lipoproteins (HDLs), along with altered HDL composition and function, may contribute to the accelerated atherosclerosis in SLE patients. Normally, HDLs play various atheroprotective roles through facilitating cholesterol efflux, inhibiting vascular inflammation, and scavenging oxidative species. However, systemic inflammation, oxidative stress, and autoimmunity in SLE patients induce changes in HDL size distribution and proteomic and lipidomic signatures. These compositional changes in HDLs result in the formation of proinflammatory, dysfunctional HDL. These lupus-altered HDLs have impaired antiatherogenic function with reduced cholesterol efflux capacities, impaired antioxidation abilities, and diminished antiinflammatory properties. In fact, dysfunctional HDL may promote atherogenesis by inducing inflammation. Thus, dysfunctional HDLs could be an important biomarker of accelerated atherosclerosis in lupus. Additionally, HDL-targeted therapies, especially infusion of reconstituted HDLs, may serve as a potential therapeutic intervention for SLE patients with CVD.

Figure 1.

Formation of dysfunctional HDL or proinflammatory (piHDL) in SLE. In SLE, multiple HDL proteomic changes occur leading to the impairment of HDL’s function. Oxidation of apoA-I methionine and tyrosine residues by chemical and enzymatic pathways leads to reduced HDL’s ability to efflux cholesterol outside the cell and neutralize oxidized lipids. Increased levels of serum amyloid A (SAA) caused displacement of apoA-I on HDL and reduced cholesterol efflux and anti-inflammatory activity. Reduced levels and activity of HDL associated PON-1 lead to the reduced anti-oxidant activity of HDL. Abbreviations: ApoA-I, apolipoprotein A-I; Met, methionine; Tyr, tyrosine; PON, paraoxonase.

Figure 2.

Formation of dysfunctional HDL and autoantibodies against HDL and apoA-I in SLE. In SLE, abnormal elevation of NETs is observed leading to endothelial cell damage. In presence of NETs increased levels of MPO, NOS, NOX, and ROS are observed causing oxidation of HDL and apoA-I. Oxidation of apoA-I and HDL induces the formation of anti-HDL and anti-apoA-I autoantibodies. Furthermore, oxidation of apoA-I at Met148 leads to conformational changes of apoA-I promoting protein misfolding, dissociation of misfolded apoA-I from HDL and formation of apoA-I amyloid fibrils. This aggregated apoA-I in more immunogenic leading to further increase in anti-apoA-I autoantibody titers. Abbreviations: ApoA-I, apolipoprotein A-I; EC, endothelial cell; SM, smooth muscle cell; NETs, neutrophil extracellular traps; MPO, myeloperoxidase; NOS, nitric oxide synthase; NOX, NADPH oxidase; Met, methionine; Tyr, tyrosine.

Figure 3.

Reconstituted HDL (rHDL) as a putative therapeutic strategy in SLE patients at risk for CVD. Infusion of rHDL in SLE may increase the level of preβ-HDL, reduce the presence of inflammatory mediators and activation of endothelial cells, enhance anti-inflammatory properties, ATF-3 activation, and facilitate cholesterol efflux capacity.