Autoimmune-mediated reduction of high-density lipoprotein–cholesterol and paraoxonase 1 activity in systemic lupus erythematosus–prone gld mice

Reverse cholesterol transport (RCT) and paraoxonase-1 (PON1)-mediated anti-oxidant activity are considered major functional properties of high-density lipoprotein (HDL) responsible for its atheroprotective effects (1,2). RCT maintains normal cholesterol homeostasis in peripheral tissues by promoting the efflux of excess cholesterol onto HDL for transport to the liver and subsequent excretion into bile and feces (3). In addition to apolipoprotein-A1 (ApoA1), the main lipid-binding protein component of HDL, HDL-associated PON1 contributes to the protective anti-inflammatory effects of HDL by reducing the generation of pro-inflammatory oxidized phospholipids during the oxidative modification of low-density lipoprotein (LDL) in the vascular wall and eliminating bioactive lipids generated under conditions of oxidative stress (2). The acute phase response (APR) is a protective systemic inflammatory reaction to infection orchestrated largely through the modulation of hepatic synthesis of specific plasma proteins by systemic increases in pro-inflammatory cytokines (4). The APR is accompanied by transient down-modulation of plasma HDL-cholesterol (HDL-C) levels, PON1 activity and HDL-associated anti-inflammatory properties (5,6). Similar reductions of HDL-C and PON1 activity have been reported in rodent models of infection and inflammation (7). Hepatic synthesis of the positive acute phase protein, serum amyloid A-1 (SAA1), is increased during the APR (4,5) and subsequently incorporated onto HDL (8). Although SAA1 incorporation onto HDL in vitro has been proposed to displace ApoA1, the major protein constituent of HDL mediating its cholesterol transport function and essential for maintaining optimal PON1 activity on HDL (9,10), it remains unclear whether SAA1 can displace ApoA1 from HDL in vivo (11). Systemic inflammation may also modulate HDL levels via transcriptional changes in the hepatic expression of major proteins involved in HDL metabolism such as ATP binding cassette (ABC) transporters and the HDL-C scavenger receptor class B type 1 (SRB1) (12,13). Studies in mice demonstrating down-modulatory effects of HDL and Liver X Receptor-dependent cholesterol efflux on lymphocyte proliferation and activation (14,15) support a scenario in which these inhibitory effects of the APR on HDL may serve to facilitate subsequent immune responses by transiently overriding the anti-inflammatory influence of HDL and attenuating RCT to optimize cholesterol pools in immune cells required for their proliferative expansion. However, if prolonged due to a failure to eliminate the inflammatory stimulus, or in the context of chronic inflammatory disease, they can result in the sustained impairment of HDL which may provoke an increased risk for atherosclerosis (16). Premature atherosclerosis remains a major cause of morbidity and mortality in patients with systemic lupus erythematosus (SLE) and other rheumatic autoimmune diseases (17). The prevalence of reduced HDL-C levels and PON1 activity in SLE patients suggests that autoimmune-mediated HDL dysfunction may be a significant factor contributing to their predisposition to premature atherosclerosis (18-20). Furthermore, elevated levels of ApoA1-binding autoantibodies have been reported in SLE patients (18,19) which may lead to premature clearance and/or functional impairment of HDL immune complexes. Although hypercholesterolemic models of atherosclerosis such as apolipoprotein-E deficient (ApoE-/-) and LDL receptor deficient (LDLR-/-) C57BL/6J mice on SLE-prone genetic backgrounds recapitulate the synergistic relationship between SLE and atherosclerosis observed in humans (21,22), characterization of autoimmune-mediated effects on HDL in these mice is hampered by the significant disruptions in normal lipoprotein metabolism and inflammatory processes caused by deficiency of ApoE or the LDL receptor (23,24). We therefore examined modifications of HDL in normolipidemic SLE-prone Fas ligand mutant C57BL/6J gld (generalized lymphoproliferative disorder) mice to determine whether modulatory effects that may be mechanistically relevant to premature atherosclerosis in SLE are recapitulated in this model and to assess their relationship to specific aspects of autoimmune disease.