title: Autoimmune-mediated reduction of high-density lipoprotein-cholesterol and paraoxonase 1 activity in systemic lupus erythematosus-prone gld mice.
abstract: OBJECTIVE
  To characterize modifications of high-density lipoprotein (HDL) in autoimmune gld mice that may be relevant to premature atherosclerosis in systemic lupus erythematosus, and to assess their relationship to specific aspects of autoimmune disease.
  
  
  METHODS
  HDL cholesterol (HDL-C), apolipoprotein A-I (Apo A-I), paraoxonase 1 (PON1) activity, hepatic gene expression, and HDL biogenesis were measured in aging female gld and wild-type congenic mice. Autoantibodies, lymphoid organs, and cytokines were analyzed by enzyme-linked immunosorbent assay, flow cytometry, and multiplex assay, respectively.
  
  
  RESULTS
  Plasma HDL-C, HDL Apo A-I, and HDL-associated PON1 activity were reduced in aging gld mice in association with the development of autoimmunity, independent of changes in hepatic Apo A-I and PON1 expression or HDL biogenesis. Hepatic induction of the acute-phase reactant serum amyloid A1 resulted in its incorporation into HDL in gld mice. Deletion of the lipid-sensitive receptor G2A in gld mice (G2A-/- gld) attenuated reductions in HDL-C and PON1 activity without altering hepatic Apo A-I and PON1 expression, HDL biogenesis, or levels of acute-phase proinflammatory cytokines. Plasma anti-Apo A-I autoantibodies were elevated in aging gld mice commensurate with detectable increases in Apo A-I immune complexes. Autoantibody levels were lower in aging G2A-/- gld mice compared with gld mice, and anti-Apo A-I autoantibody levels were significantly related to HDL-C concentrations (r=-0.645, P<0.00004) and PON1 activity (r=-0.555, P<0.0007) among autoimmune gld and G2A-/- gld mice.
  
  
  CONCLUSIONS
  Autoantibodies against Apo A-I contribute to reducing HDL-C and PON1 activity in autoimmune gld mice independently of hepatic HDL biogenesis, suggesting that functional impairment and premature clearance of HDL immune complexes may be principal mechanisms involved.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL 35294-2170, USA.
authors.forename: Roshni
authors.initials: R
authors.lastname: Srivastava
authors.forename: Shaohua
authors.initials: S
authors.lastname: Yu
authors.forename: Brian W
authors.initials: BW
authors.lastname: Parks
authors.forename: Leland L
authors.initials: LL
authors.lastname: Black
authors.forename: Janusz H
authors.initials: JH
authors.lastname: Kabarowski
mesh_terms: D000375:Aging / Q000276:immunology / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D043303:Aryldialkylphosphatase / Q000276:immunology / Q000378:metabolism*; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity / Q000502:physiology*; D015153:Blotting, Western; D008076:Cholesterol, HDL / Q000276:immunology / Q000378:metabolism*; D016207:Cytokines / Q000097:blood; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology / Q000378:metabolism; D051379:Mice; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D001323:Autoantibodies; D008076:Cholesterol, HDL; D016207:Cytokines; D043303:Aryldialkylphosphatase