Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients

Morrisett, Joel D.; Abdel-Fattah, Ghada; Kahan, Barry D.

doi:10.1016/s0041-1345(03)00233-1

Cited by 81 publications

(68 citation statements)

References 18 publications

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“…We have also observed a reduction in VLDL and LDLr in hepatocyte cultures (not published). In addition, some studies have also reported that sirolimus alters the insulin signaling pathway by increasing adipose tissue lipase activity and/or decreasing lipoprotein lipase activity, resulting in increased hepatic synthesis of triglyceride, increased secretion of VLDL, and increased hypertriglyceridemia (23). However, sirolimus also significantly increased cholesterol efflux from the cells through the ABCA1 and ABCG1 pathways as demonstrated here, which may reduce intracellular cholesterol level and increase HDL formation, which protects against atherosclerosis.…”

Section: Discussionsupporting

confidence: 60%

“…Our results may also partly explain some dose-dependent adverse effects of sirolimus, especially hyperlipidemia with a high plasma VLDL and LDL concentration in transplant patients after sirolimus treatment (13,21,22). Sirolimus reduces lipids influx to peripheral cells such as VSMCs by inhibiting receptor-mediated uptake of LDL and VLDL, the carriers of cholesterol and triglyceride, respectively.…”

Section: Discussionmentioning

confidence: 61%

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Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells

Liu¹,

Ruan²,

Powis³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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Ma KL, Ruan XZ, Powis SH, Moorhead JF, Varghese Z. Antiatherosclerotic effects of sirolimus on human vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 292: H2721-H2728, 2007. First published February 23, 2007 doi:10.1152/ajpheart.01174.2006.-Sirolimus is a potent immunosuppressive agent and has an anti-atherosclerotic effect through its anti-proliferative property. The present study was undertaken to investigate the effect of sirolimus on intracellular cholesterol homeostasis in human vascular smooth muscle cells (VSMCs) in the presence of inflammatory cytokine IL-1␤. We explored the effect of sirolimus on the lipid accumulation of VSMCs in the presence of IL-1␤, using Oil Red O staining and quantitative measurement of intracellular cholesterol. The effect of sirolimus on the gene and protein expression of lipoprotein receptors and ATP binding cassettes (ABCA1 and ABCG1) was examined by real-time PCR and Western blotting, respectively. Furthermore, the effect of sirolimus on cholesterol efflux from VSMCs in the presence or absence of IL-1␤ was also investigated using [ 3 H] cholesterol efflux. Finally, we examined the effect of sirolimus on the production of inflammatory cytokines in VSMCs using ELISA. Sirolimus reduced intracellular lipid accumulation in VSMCs mediated by IL-1␤ possibly due to the reduction of expression of low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) receptors. Sirolimus increased cholesterol efflux from VSMCs and overrode the suppression of cholesterol efflux induced by IL-1␤. Sirolimus also increased ABCA1 and ABCG1 genes expression, even in the presence of IL-1␤. We further confirmed that sirolimus inhibited mRNA and protein expression of inflammatory cytokines IL-6, tumor necrosis factor-␣, IL-8, and monocyte chemoattractant protein-1. Inhibition of lipid uptake together with increasing cholesterol efflux and the inhibition of inflammatory cytokines are all important aspects of the anti-atherosclerotic effects of sirolimus on VSMCs. cholesterol homeostasis; foam cell; inflammatory cytokine ATHEROSCLEROSIS is a multifactorial disease; disordered lipid metabolism and chronic inflammation are important contributory factors (16,32). Vascular smooth muscle cells (VSMCs) play a key role during the pathogenesis of vascular lesion, although they are not always the main cell component of atherosclerotic lesions, especially in the early stages. In normal vessels, the majority of VSMCs reside in the media, where they are quiescent and possess a "contractile" phenotype characterized by the abundance of actin-and myosin-containing filaments (4, 33). In disease states, VSMCs reenter the cell cycle, proliferate, and migrate from media to intima (33). After vessel injury, intimal VSMCs have a synthetic phenotype, characterized by hyperplasia or hypertrophy and matrix protein accumulation in the intima and/or media with or without lipid deposition, resulting in thickening and stiffness of the arterial wall. Foam cells have traditionally been regarded as being derived f...

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Section: Discussionsupporting

confidence: 60%

Section: Discussionmentioning

confidence: 61%

Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells

Liu¹,

Ruan²,

Powis³

et al. 2007

American Journal of Physiology-Heart and Circulatory Physiology

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“…demia that involves hepatic overproduction of TG ( 32,33 ). Rapamycin treatment of McA cells did not affect the increased TG secretion observed in ABCA1 versus control siRNA-treated cells (supplemental Fig.…”

Section: Discussionmentioning

confidence: 91%

“…Several studies have reported that control of VLDL secretion can be achieved through mTOR ( 32,33 ) and MEK/ERK signaling ( 34 ). We investigated whether MEK/ ERK phosphorylation was mediating the increase in VLDL-TG secretion when ABCA1 was silenced.…”

Section: Elevated Tg Secretion In Abca1-silenced Mca Rat Hepatoma Celmentioning

confidence: 99%

A novel role for ABCA1-generated large pre- migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

Chung

Gebre

Seo

et al. 2010

The Journal of Lipid Research

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ABCA1 is a membrane protein that transports phospholipid (PL) and free cholesterol (FC) across cell membranes, to combine with lipid-free apolipoprotein (apo) A-I , forming nascent HDL particles ( 1 ). Mutations in ABCA1 that inactivate its function cause Tangier disease, which is characterized by a severe HDL defi ciency, rapid clearance of apoA-I from plasma, deposition of sterol in macrophage-rich tissues, and premature coronary heart disease ( 2-5 ). ABCA1 is expressed in many cells, but hepatocytes are the single most important cell type in determining plasma HDL concentrations, contributing 70-80% of the HDL pool in mice ( 6, 7 ). Recently, we have shown that ABCA1 expression is necessary and suffi cient for formation of heterogeneous-sized pre-␤ migrating nascent HDL subspecies (pre-␤ 1, 2, 3, and 4 HDL), which vary in size from 7.1 to 15.7 nm ( 8 ). Although electrophoretic mobility (pre-␤ vs. ␣ migration) of discoidal nascent HDLs is dependent on cell type and culture conditions, similar distinct-sized subspecies of nascent HDL are formed by most cell types tested, including fi broblasts ( 9, 10 ), macrophages, hepatocytes, and ABCA1-expressing human embryonic kidney (HEK)293 cells ( 11 ). The importance of nascent HDL size heterogeneity in the physiology and pathophysiology of HDL metabolism is poorly understood.ABCA1 expression also affects plasma VLDL and LDL concentrations. In addition to the near absence of plasma HDL, many homozygous Tangier disease patients have Abstract In Tangier disease, absence of ATP binding cassette transporter A1 (ABCA1) results in reduced plasma HDL and elevated triglyceride (TG) levels. We hypothesized that hepatocyte ABCA1 regulates VLDL TG secretion through nascent HDL production. Silencing of ABCA1 expression in oleate-stimulated rat hepatoma cells resulted in: 1 ) decreased large nascent HDL (>10 nm diameter) and increased small nascent HDL (<10 nm) formation, 2 ) increased large buoyant VLDL1 particle secretion, and 3 ) decreased phosphatidylinositol-3 (PI3) kinase activation. Nascent HDL-containing conditioned medium from rat hepatoma cells or HEK293 cells transfected with ABCA1 was effective in increasing PI3 kinase activation and reducing VLDL TG secretion in ABCA1-silenced hepatoma cells. Addition of isolated large nascent HDL particles to ABCA1-silenced hepatoma cells inhibited VLDL TG secretion to a greater extent than small nascent HDL. Similarly, addition of recombinant HDL, but not human plasma HDL, was effective in attenuating TG secretion and increasing PI3 kinase activation in ABCA1-silenced cells. Collectively, these data suggest that large nascent HDL particles, assembled by hepatic ABCA1, generate a PI3 kinase-mediated autocrine signal that attenuates VLDL maturation and TG secretion. This pathway may explain the elevated plasma TG concentration that occurs in most Tangier subjects and may also account, in part, for the inverse relationship between plasma HDL and TG concentrations in individuals with compromised ABCA1 function. -Chung, S., A. K. Gebre...

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“…For example, hyperlipidemia is commonly seen in patients treated with temsirolimus, the mechanism behind which may be secondary to the inhibition of Akt in adipose tissue by rapamycin. 82 In normal adipose cells, Akt function is dependent on insulin stimulation and (once activated) can suppress lipolysis. In rapamycin-treated cells, Akt inhibition can result in increased lipolysis and an accumulation of free fatty acids, resulting in the hepatic generation of triglycerides.…”

Section: Select Adverse Effects Of Temsirolimus In MCLmentioning

confidence: 99%

Temsirolimus in the treatment of relapsed or refractory mantle cell lymphoma

Samad¹,

Younes

2010

OTT

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Mantle cell lymphoma (MCL) is a rare and aggressive subtype of lymphoma associated with a poor prognosis. Chemotherapy is the mainstay of frontline treatment for patients with this disease. Despite high response rates to combination chemotherapy regimens, the majority of patients relapse within a few years of treatment. Therefore, finding efficacious treatments for relapsed or refractory disease has become a growing area of clinical research. The mammalian target of rapamycin (mTOR) is responsible for integrating cell signals from growth factors, hormones, and nutrients and communicating energy status. Scientific research on aberrant molecular pathways in cancer has revealed that several proteins along the mTOR pathway may be upregulated in this and other types of lymphoma. Temsirolimus is the first mTOR inhibitor that has shown clinical efficacy in treating MCL that has relapsed after frontline treatments.

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Sirolimus changes lipid concentrations and lipoprotein metabolism in kidney transplant recipients

Cited by 81 publications

References 18 publications

Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells

Anti-atherosclerotic effects of sirolimus on human vascular smooth muscle cells

A novel role for ABCA1-generated large pre- migrating nascent HDL in the regulation of hepatic VLDL triglyceride secretion

Temsirolimus in the treatment of relapsed or refractory mantle cell lymphoma

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