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

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

doi:10.1194/jlr.m100392-jlr200

Cited by 264 publications

(118 citation statements)

References 34 publications

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“…However, despite this local positive effect, it exacerbated pre-existing hypercholesterolemia and hypertriglyceridemia raising concerns about its possible clinical use in atherosclerosis. Thus, some studies in humans showed that at this high-dosage sirolimus indeed could elevate plasma lipids and lipoprotein levels in renal transplantation patients (Hoogeveen et al, 2001;Morriset et al, 2002;Morales, 2005).…”

Section: Discussionmentioning

confidence: 99%

Low‐dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor

Zhao

Ding

Cyrus

et al. 2009

British J Pharmacology

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Background and purpose:Chronic proliferative responses of different vascular cell types have been involved in the pathogenesis of atherosclerosis. However, their functional role remains to be established. Sirolimus reduces neointimal proliferation after balloon angioplasty and chronic graft vessel disease. These studies were undertaken to investigate the effects of this anti-proliferative drug on atherogenesis. Experimental approach: Low-density lipoprotein receptor-deficient (LDL r-KO) mice on a cholesterol-rich diet were randomized to receive placebo or sirolimus (0.1; 0.3; or 1 mg·kg -1 ) in their diet for 8 or 16 weeks. Results: In both studies, plasma levels of the drug increased in a dose-dependent fashion, animals gained weight normally and, among groups, plasma lipids levels did not differ significantly. Compared with placebo, plasma levels of interleukin-6, monocyte chemoattractant protein-1, interferon g, tumour necrosis factor a and CD40, and their mRNA levels in aortic tissue were significantly reduced in sirolimus-treated mice. This effect resulted in a significant and dose-dependent reduction in atherosclerotic lesions, in both the root and aortic tree. Also these lesions contained less monocyte/macrophages and smooth muscle cells, but more collagen. Conclusions and implications:The present results demonstrated that at low doses, sirolimus was an effective and safe anti-atherogenic agent in the LDL r-KO mice. It attenuated the progression of atherosclerosis and modulated the plaque phenotype by reducing the pro-inflammatory vascular responses typical of the disease.

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Section: Discussionmentioning

confidence: 99%

Low‐dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor

Zhao

Ding

Cyrus

et al. 2009

British J Pharmacology

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“…Our previous work demonstrated that rapamycin administration induces hypertriglyceridemia in organ transplant patients [11], and increases TAG and plasma FFA in guinea pigs [25]. Here, we test the hypothesis that rapamycin promotes TAG lipolysis in cultured murine 3T3-L1 adipocytes.…”

Section: Introductionmentioning

confidence: 85%

“…Rapamycin administration incurs adverse side effects, however. Various clinical trials have documented the development of hypertriglyceridemia or hypercholesterolemia in renal, hepatic, cardiac, and islet transplant patients [11,12]. Additionally, rapamycin has also been shown to elevate serum free fatty acid (FFA) levels and induce glucose intolerance [13] in transplant patients as well as in mice lacking the mTORC1 downstream target S6K1 [14].…”

Section: Introductionmentioning

confidence: 99%

mTORC1 Inhibition via Rapamycin Promotes Triacylglycerol Lipolysis and Release of Free Fatty Acids in 3T3‐L1 Adipocytes

Soliman

Acosta-Jaquez

Fingar

2010

Lipids

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Signaling by mTOR complex 1 (mTORC1) promotes anabolic cellular processes in response to growth factors, nutrients, and hormonal cues. Numerous clinical trials employing the mTORC1 inhibitor rapamycin (aka sirolimus) to immuno-suppress patients following organ transplantation have documented the development of hypertriglyceridemia and elevated serum free fatty acids (FFA). We therefore investigated the cellular role of mTORC1 in control of triacylglycerol (TAG) metabolism using cultured murine 3T3-L1 adipocytes. We found that treatment of adipocytes with rapamycin reduced insulin-stimulated TAG storage ~50%. To determine whether rapamycin reduces TAG storage by upregulating lipolytic rate, we treated adipocytes in the absence and presence of rapamycin and isoproterenol, a β2-adrenergic agonist that activates the cAMP/protein kinase A (PKA) pathway to promote lipolysis. We found that rapamycin augmented isoproterenol-induced lipolysis without altering cAMP levels. Rapamycin enhanced the isoproterenol-stimulated phosphorylation of hormone sensitive lipase (HSL) on Ser-563 (a PKA site), but had no effect on the phosphorylation of HSL S565 (an AMPK site). Additionally, rapamycin did not affect the isoproterenol-mediated phosphorylation of perilipin, a protein that coats the lipid droplet to initiate lipolysis upon phosphorylation by PKA. These data demonstrate that inhibition of mTORC1 signaling synergizes with the β-adrenergic-cAMP/PKA pathway to augment phosphorylation of HSL to promote hormone-induced lipolysis. Moreover, they reveal a novel metabolic function for mTORC1; mTORC1 signaling suppresses lipolysis, thus augmenting TAG storage.

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“…A high-fat meal increased the bioavailability in healthy subjects by 35% [23] after administration of an oral solution and by 23% after administration of a tablet [11]. Patients with dyslipidaemia may habitually consume higher fat meals,which may then result in increased absorption of sirolimus.Furthermore,sirolimus itself can increase the high, low, intermediate, very-lowdensity lipoproteins and TG levels [72,73]. Furthermore, because of its hydrophobic nature, sirolimus is widely distributed in the lipid membranes of body tissues as well as erythrocytes.…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients

Jiao

Shi

et al. 2009

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT?• Sirolimus is an immunosuppressive agent used for the prophylaxis of renal allograft rejection.• Several conventional pharmacokinetic and population pharmacokinetic studies have been conducted to assess the pharmacokinetic characteristics of sirolimus in White or African-American recipients. WHAT THIS STUDY ADDS?• The population pharmacokinetics of sirolimus in Chinese adult renal transplant recipients was characterized for the first time.• New drug-drug interactions between herbal medicines and sirolimus were identified as the covariates on sirolimus clearance. AIMSThis study was aimed at determining the population pharmacokinetics of sirolimus and identifying factors that explain pharmacokinetic variability in de novo Chinese adult renal transplant patients. METHODSData were retrospectively extracted from a formal multicentre clinical trial, which was originally designed to evaluate the safety and efficacy of ciclosporin dose reduction and ciclosporin elimination in patients receiving sirolimus. All patients received 12-month treatment, i.e. induction therapy with ciclosporin, sirolimus and corticosteroids during the first 3 months followed by either ciclosporin dose reduction or ciclosporin discontinuation thereafter. Eight-hundred and four sirolimus trough blood concentrations (C 0) from 112 patients were used to develop a population pharmacokinetic model using the NONMEM program. A one-compartment model with first-order absorption and elimination was selected as the base model. The influence of demographic characteristics, biochemical and haematological indices, ciclosporin daily dose, ciclosporin C0 as well as other commonly used co-medications were explored. RESULTSThe typical values with interindividual variability for apparent clearance (CL/F) and apparent volume of distribution (V/F) were 10.1 l h -1 (23.8%) and 3670 l (56.7%), respectively. The residual variability was 29.9%. CL/F decreased significantly with silymarin or glycyrrhizin co-therapy in hepatically impaired patients, and with increasing total cholesterol levels or ciclosporin C0. Moreover, CL/F increased nonlinearly with increasing sirolimus daily dose. The median parameter estimates from a nonparametric bootstrap procedure were comparable and within 5% of the estimates from NONMEM. CONCLUSIONSThese results provide important information for clinicians to optimize sirolimus regimens in Chinese renal transplant patients.

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

Cited by 264 publications

References 34 publications

Low‐dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor

Low‐dose oral sirolimus reduces atherogenesis, vascular inflammation and modulates plaque composition in mice lacking the LDL receptor

mTORC1 Inhibition via Rapamycin Promotes Triacylglycerol Lipolysis and Release of Free Fatty Acids in 3T3‐L1 Adipocytes

Population pharmacokinetics of sirolimus in de novo Chinese adult renal transplant patients

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