Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients

Joel D. Morrisett, Ghada Soliman, Ron Hoogeveen, Eddie Mitchell, Christie M. Ballantyne, Henry J. Pownall, Antone R. Opekun, Jonathon S. Jaffe, Suzanne Oppermann, Barry D. Kahan

Research output: Contribution to journalArticle

205 Citations (Scopus)

Abstract

Sirolimus (Rapammune®, rapamycin, RAPA) is a potent immunosuppressive drug that reduces renal transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment, and frequently leads to cardiovascular disease. This study was undertaken to determine the repeatability, reversibility, and dose dependence of the plasma lipid and apolipoprotein altering effects of sirolimus, and to elucidate the mechanism by which sirolimus induces hypertriglyceridemia in some renal transplant patients. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/day sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apolipoprotein, and sirolimus levels. During sirolimus administration, mean total plasma cholesterol increased from 214 mg/dl to 322 mg/dl (+50%; range 25-92%); LDL-cholesterol levels followed a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dl (+95%; range 9-254%). ApoB-100 concentration rose from 124 to 160 mg/dl (+28%; P < 0.05). ApoC-III level increased from 28.9 to 55.5 mg/dl, +92%; (P < 0.013). These lipid and apolipoprotein changes were found to be repeatable, reversible, and dose dependent. [13C4]palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3%). Incorporation of [13C4]palmitate into triglycerides of VLDL, IDL, and LDL was decreased 38.3%, 42,1%, and 38.4%, respectively, by sirolimus treatment of these patients. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity and/or decrease lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.

Original languageEnglish (US)
Pages (from-to)1170-1180
Number of pages11
JournalJournal of Lipid Research
Volume43
Issue number8
StatePublished - Aug 1 2002

Fingerprint

Transplants
Sirolimus
Metabolism
Lipoproteins
Fatty Acids
Kidney
Lipids
Plasmas
Apolipoproteins
Hypertriglyceridemia
Palmitates
Hyperlipidemias
Triglycerides
Apolipoprotein C-III
Patient treatment
Apolipoprotein B-100
Lipoprotein Lipase
Graft Rejection
Therapeutics
Immunosuppressive Agents

Keywords

  • Cholesterol
  • Rapamycin
  • Triglyceride

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology
  • Cell Biology

Cite this

Morrisett, J. D., Soliman, G., Hoogeveen, R., Mitchell, E., Ballantyne, C. M., Pownall, H. J., ... Kahan, B. D. (2002). Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. Journal of Lipid Research, 43(8), 1170-1180.

Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. / Morrisett, Joel D.; Soliman, Ghada; Hoogeveen, Ron; Mitchell, Eddie; Ballantyne, Christie M.; Pownall, Henry J.; Opekun, Antone R.; Jaffe, Jonathon S.; Oppermann, Suzanne; Kahan, Barry D.

In: Journal of Lipid Research, Vol. 43, No. 8, 01.08.2002, p. 1170-1180.

Research output: Contribution to journalArticle

Morrisett, JD, Soliman, G, Hoogeveen, R, Mitchell, E, Ballantyne, CM, Pownall, HJ, Opekun, AR, Jaffe, JS, Oppermann, S & Kahan, BD 2002, 'Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients', Journal of Lipid Research, vol. 43, no. 8, pp. 1170-1180.
Morrisett JD, Soliman G, Hoogeveen R, Mitchell E, Ballantyne CM, Pownall HJ et al. Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. Journal of Lipid Research. 2002 Aug 1;43(8):1170-1180.
Morrisett, Joel D. ; Soliman, Ghada ; Hoogeveen, Ron ; Mitchell, Eddie ; Ballantyne, Christie M. ; Pownall, Henry J. ; Opekun, Antone R. ; Jaffe, Jonathon S. ; Oppermann, Suzanne ; Kahan, Barry D. / Effects of sirolimus on plasma lipids, lipoprotein levels, and fatty acid metabolism in renal transplant patients. In: Journal of Lipid Research. 2002 ; Vol. 43, No. 8. pp. 1170-1180.
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abstract = "Sirolimus (Rapammune{\circledR}, rapamycin, RAPA) is a potent immunosuppressive drug that reduces renal transplant rejection. Hyperlipidemia is a significant side effect of sirolimus treatment, and frequently leads to cardiovascular disease. This study was undertaken to determine the repeatability, reversibility, and dose dependence of the plasma lipid and apolipoprotein altering effects of sirolimus, and to elucidate the mechanism by which sirolimus induces hypertriglyceridemia in some renal transplant patients. Six patients with renal allografts maintained on cyclosporine A and prednisone were selected on the basis of their previous hyperlipidemic response to short term (14 days) sirolimus administration. For longer-term treatment, each patient was started on 10 mg/day sirolimus and continued as tolerated for 42 days to reinduce hyperlipidemia. Timed blood samples were analyzed for lipid, apolipoprotein, and sirolimus levels. During sirolimus administration, mean total plasma cholesterol increased from 214 mg/dl to 322 mg/dl (+50{\%}; range 25-92{\%}); LDL-cholesterol levels followed a similar pattern. Mean triglyceride level rose from 227 to 432 mg/dl (+95{\%}; range 9-254{\%}). ApoB-100 concentration rose from 124 to 160 mg/dl (+28{\%}; P < 0.05). ApoC-III level increased from 28.9 to 55.5 mg/dl, +92{\%}; (P < 0.013). These lipid and apolipoprotein changes were found to be repeatable, reversible, and dose dependent. [13C4]palmitate metabolic studies in four patients with hypertriglyceridemia indicated that the free fatty acid pool was expanded by sirolimus treatment (mean = 42.3{\%}). Incorporation of [13C4]palmitate into triglycerides of VLDL, IDL, and LDL was decreased 38.3{\%}, 42,1{\%}, and 38.4{\%}, respectively, by sirolimus treatment of these patients. These results suggest that sirolimus alters the insulin signaling pathway so as to increase adipose tissue lipase activity and/or decrease lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia.",
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