{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T09:30:51Z","timestamp":1789119051087,"version":"build-2803163510"},"reference-count":41,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"7","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["ATVB"],"published-print":{"date-parts":[[2016,7]]},"abstract":"<jats:sec><jats:title>Objective\u2014<\/jats:title><jats:p>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)\u2013mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using<jats:italic>Ldlr<\/jats:italic>-knockout mice (<jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>).<\/jats:p><\/jats:sec><jats:sec><jats:title>Approach and Results\u2014<\/jats:title><jats:p><jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>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<jats:italic>Ldlr<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low\u2013density 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\u2013tandem mass spectrometry suggested a predominant effect of CsA on increased very low\u2013density lipoprotein\u2013IDL\/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 [<jats:sup>14<\/jats:sup>C]cholesteryl oleate and glycerol tri[<jats:sup>3<\/jats:sup>H]oleate-double-labeled very low\u2013density lipoprotein\u2013like 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.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions\u2014<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1161\/atvbaha.115.307030","type":"journal-article","created":{"date-parts":[[2016,5,6]],"date-time":"2016-05-06T05:50:10Z","timestamp":1462513810000},"page":"1338-1349","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":31,"title":["Low-Density Lipoprotein Receptor\u2013Dependent and Low-Density Lipoprotein Receptor\u2013Independent Mechanisms of Cyclosporin A\u2013Induced Dyslipidemia"],"prefix":"10.1161","volume":"36","author":[{"given":"Maaike","family":"Kockx","sequence":"first","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elias","family":"Glaros","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Betty","family":"Leung","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theodore W.","family":"Ng","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jimmy F.P.","family":"Berb\u00e9e","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Virginie","family":"Deswaerte","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Nawara","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmel","family":"Quinn","sequence":"additional","affiliation":[{"name":"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,..."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerry-Anne","family":"Rye","sequence":"additional","affiliation":[{"name":"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; 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