Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia

Maaike Kockx, Elias N Glaros, Betty Leung, Theodore W Ng, Jimmy F.P. Berbée, Virginie Deswaerte, Diana Nawara, Carmel Quinn, Kerry-Anne Rye, Wendy Jessup, Patrick C.N. Rensen, Peter J. Meikle, Leonard Kritharides

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Abstract

Objective-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-/-). Approach and Results-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 [14C]cholesteryl oleate and glycerol tri[3H]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. Conclusions-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.

Original languageEnglish
Pages (from-to)1338-1349
Number of pages12
JournalArteriosclerosis, Thrombosis and Vascular Biology
Volume36
Issue number7
DOIs
Publication statusPublished - 1 Jul 2016
Externally publishedYes

Keywords

  • apolipoprotein C-III
  • Cyclosporin A
  • Hyperlipidemia
  • Immunosuppression
  • Lipolysis
  • Proprotein convertase subtilisin/kexin type 9
  • Triglycerides

Cite this

Kockx, M., Glaros, E. N., Leung, B., Ng, T. W., Berbée, J. F. P., Deswaerte, V., Nawara, D., Quinn, C., Rye, K-A., Jessup, W., Rensen, P. C. N., Meikle, P. J., & Kritharides, L. (2016). Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia. Arteriosclerosis, Thrombosis and Vascular Biology, 36(7), 1338-1349. https://doi.org/10.1161/ATVBAHA.115.307030