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The study of the effect of immunosuppressive drugs on lipid metabolism

University of British Columbia

Introduction: Lipid abnormalities including increased total cholesterol, triglycerides, and lowdensity lipoprotein-cholesterol have been frequently reported in renal transplantation and could be involved in the high frequency of cardiovascular disease in this population. Immunosuppressive therapy appears to be a main factor that influences the post-transplant lipid profile. Cyclosporine A (CsA), rapamycin (RAPA), tacrolimus (TAC) and mycophenolate mofetil (MMF) are commonly used immunosuppressant in solid organ transplant patients. Several of these immunosuppressive agents including CsA, RAPA and TAC appear to have a significant effect on patient lipid level. Although RAPA does not seem to cause nephrotoxicity as commonly seen in patients treated with CsA or TAC, it seems to be associated with an incremental increase in triglyceride level. However, the immunosuppressive-induced hyperlipidemia has not been sufficiently described. Purpose: Our aim was to determine the effects of these drugs in vitro on key regulatory enzymes of lipid metabolism; Cholesteryl Ester Transfer Protein (CETP), hepatic lipase (HL) and lipoprotein lipase (LPL) activity within human plasma, as well as the in vivo effects of TAC on these enzymes in renal transplant patients. In addition, we also investigated the effects of RAPA and TAC on cholesterol efflux from human THP-l macrophages. Methods: The effects of CsA, TAC, RAPA and MMF on CETP, HL and LPL activity were first determined in vitro in human normolipidemic plasma and post-heparin normal human plasma, respectively. We further investigated the in vivo effects of TAC on these enzymes activities in renal transplant patients for one month following transplantation. The cholesterol efflux study was conducted independently to assess the effects of RAPA and TAC on ApoA-I- and HDL-mediated cholesterol efflux from human THP-l macrophages, as well as adenosine-triphosphate binding cassette (ABC)Al and ABCG1 protein expressions in these cells. Results: Our in vitro CETP study showed that CsA and RAPA induced CETP activity in human normolipidemic plasma in a dose-dependant manner. Although, none of these drugs, CsA, TAC, RAPA and MMF affected in vitro HL activity, these drugs suppressed the LPL activity in the post-heparin plasma. Unlike TAC, RAPA was shown to decrease apoAl-mediated cholesterol efflux and ABCA1 protein expression in human THP-l macrophages. In agreement with our in vitro result, our clinical study demonstrated that TAC significantly increased triglyceride levels and reduced the LPL activity in the renal transplant patients, regardless of the patients were on statin or not. Conclusions: These findings suggest that the increase in CETP activity, suppression in LPL activity and inhibition in the cholesterol efflux following either CsA, RAPA or TAC treatments observed in the present study may be associated with hypercholesterolemia and hypertriglyceridemia seen in patients administered these drugs.

Thesis/Dissertation

application/pdf

2009-04-27

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/7593

Pathology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/