title: Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia.
abstract: Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)).
  
  
  
  Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9.
  
  
  
  We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA.
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Maaike
authors.initials: M
authors.lastname: Kockx
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Elias
authors.initials: E
authors.lastname: Glaros
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Betty
authors.initials: B
authors.lastname: Leung
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Ng
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Jimmy F P
authors.initials: JF
authors.lastname: Berbée
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Virginie
authors.initials: V
authors.lastname: Deswaerte
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Diana
authors.initials: D
authors.lastname: Nawara
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Carmel
authors.initials: C
authors.lastname: Quinn
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Wendy
authors.initials: W
authors.lastname: Jessup
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Patrick C N
authors.initials: PC
authors.lastname: Rensen
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Meikle
authors.affiliation: From the ANZAC Research Institute (M.K., D.N., W.J., L.K.) and Department of Cardiology (L.K.), Concord Hospital, University of Sydney, Sydney, Australia; Centre for Vascular Research (E.G., C.Q.) and Department of Pathology (B.L.), University of New South Wales, Sydney, Australia; Baker IDI Heart and Diabetes Institute, Melbourne, Australia (T.W.N., P.J.M.); Department of Medicine, Division Endocrinology, and Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Centre, Leiden, The Netherlands (J.F.P.B., P.C.N.R.); Centre for Innate Immunity and Infectious Diseases, Hudson Institute of Medical Research, Clayton, Australia (V.D.); Lipid Research Group, School of Medical Sciences, University of New South Wales Australia, Sydney, Australia (K.-A.R.). leonard.kritharides@sydney.edu.au.
authors.forename: Leonard
authors.initials: L
authors.lastname: Kritharides
mesh_terms: D000818:Animals; D053305:Apolipoprotein C-III / Q000097:blood; D015415:Biomarkers / Q000097:blood; D002788:Cholesterol Esters / Q000378:metabolism; D016572:Cyclosporine; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D006949:Hyperlipidemias / Q000097:blood / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism; D008071:Lipoprotein Lipase / Q000097:blood; D008075:Lipoproteins, HDL / Q000097:blood; D053419:Lipoproteins, IDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010641:Phenotype; D000071449:Proprotein Convertase 9 / Q000097:blood; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014304:Triolein / Q000378:metabolism
chemical_list: D053305:Apolipoprotein C-III; D015415:Biomarkers; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; D053419:Lipoproteins, IDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D014304:Triolein; C014409:cholesteryl oleate; D016572:Cyclosporine; D008071:Lipoprotein Lipase; C472126:Pcsk9 protein, mouse; D000071449:Proprotein Convertase 9
keywords: apolipoprotein C-III; cyclosporin A; hyperlipidemia; immunosuppression; lipolysis; proprotein convertase subtilisin/kexin type 9; triglycerides