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

Keywords

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

Cite this

Kockx, Maaike ; Glaros, Elias N ; Leung, Betty ; Ng, Theodore W ; Berbée, Jimmy F.P. ; Deswaerte, Virginie ; Nawara, Diana ; Quinn, Carmel ; Rye, Kerry-Anne ; Jessup, Wendy ; Rensen, Patrick C.N. ; Meikle, Peter J. ; Kritharides, Leonard. / Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia. In: Arteriosclerosis, Thrombosis and Vascular Biology. 2016 ; Vol. 36, No. 7. pp. 1338-1349.
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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.",
keywords = "apolipoprotein C-III, Cyclosporin A, Hyperlipidemia, Immunosuppression, Lipolysis, Proprotein convertase subtilisin/kexin type 9, Triglycerides",
author = "Maaike Kockx and Glaros, {Elias N} and Betty Leung and Ng, {Theodore W} and Berb{\'e}e, {Jimmy F.P.} and Virginie Deswaerte and Diana Nawara and Carmel Quinn and Kerry-Anne Rye and Wendy Jessup and Rensen, {Patrick C.N.} and Meikle, {Peter J.} and Leonard Kritharides",
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Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia. / Kockx, Maaike; Glaros, Elias N; Leung, Betty; Ng, Theodore W; Berbée, Jimmy F.P.; Deswaerte, Virginie; Nawara, Diana; Quinn, Carmel; Rye, Kerry-Anne; Jessup, Wendy; Rensen, Patrick C.N.; Meikle, Peter J.; Kritharides, Leonard.

In: Arteriosclerosis, Thrombosis and Vascular Biology, Vol. 36, No. 7, 01.07.2016, p. 1338-1349.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Low-Density Lipoprotein Receptor-Dependent and Low-Density Lipoprotein Receptor-Independent Mechanisms of Cyclosporin A-Induced Dyslipidemia

AU - Kockx, Maaike

AU - Glaros, Elias N

AU - Leung, Betty

AU - Ng, Theodore W

AU - Berbée, Jimmy F.P.

AU - Deswaerte, Virginie

AU - Nawara, Diana

AU - Quinn, Carmel

AU - Rye, Kerry-Anne

AU - Jessup, Wendy

AU - Rensen, Patrick C.N.

AU - Meikle, Peter J.

AU - Kritharides, Leonard

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - apolipoprotein C-III

KW - Cyclosporin A

KW - Hyperlipidemia

KW - Immunosuppression

KW - Lipolysis

KW - Proprotein convertase subtilisin/kexin type 9

KW - Triglycerides

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U2 - 10.1161/ATVBAHA.115.307030

DO - 10.1161/ATVBAHA.115.307030

M3 - Article

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EP - 1349

JO - Arteriosclerosis, Thrombosis and Vascular Biology

JF - Arteriosclerosis, Thrombosis and Vascular Biology

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