EFFECT OF SIROLIMUS ON THE METABOLISM OF ApoB100- CONTAINING LIPOPROTEINS IN RENAL TRANSPLANT PATIENTS1

Hoogeveen, Ron C.; Ballantyne, Christie M.; Pownall, Henry J.; Opekun, Antone R.; Hachey, David L.; Jaffe, Jonathan S.; Oppermann, Suzanne; Kahan, Barry D.; Morrisett, Joel D.

doi:10.1097/00007890-200110150-00011

Cited by 117 publications

(65 citation statements)

References 24 publications

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“…In that study, treatment with sirolimus was associated with a 70% decrease in VLDL-apoB100 catabolism and a 28% decrease in IDL-apoB100 catabolism (56). In line with these kinetic results, a significant decrease in post-heparin lipoprotein lipase (LPL) activity (the major enzyme responsible for triglyceride catabolism) was observed in patients showing sirolimus-induced hypertriglyceridemia (56) (Fig. 2).…”

Section: Effects Of Mtor Inhibitors On Lipids "supporting

confidence: 59%

“…It has been postulated that this increase in free fatty acids may increase hepatic VLDL production, but such increase in VLDL production has not been clearly shown in human kinetic studies (56). As far as LDL cholesterol is concerned, a kinetic study performed in renal transplant patients has shown that treatment with sirolimus was associated with a 68% decrease in LDL-apoB100 catabolism (56). It has been shown in vitro with HepG2 cells that sirolimus reduced LDL receptor (LDLr) expression leading to diminished LDL uptake (58) (Fig.…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 98%

“…In addition, rapamycin has been shown to promote fatty acid b-oxidation while decreasing fatty acid flux into anabolic storage pathways in primary cultures of rat hepatocytes, suggesting that the hyperlipidemia associated with rapamycin is not likely due to increased lipid hepatic synthesis but rather due to delayed peripheral clearance (25). Indeed, in kidney transplant recipients with sirolimus-induced hypertriglyceridemia, it has been shown with an in vivo kinetic study that hypertriglyceridemia was mostly due to decreased very-LDL (VLDL) catabolism (56). In that study, treatment with sirolimus was associated with a 70% decrease in VLDL-apoB100 catabolism and a 28% decrease in IDL-apoB100 catabolism (56).…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 99%

“…Indeed, in kidney transplant recipients with sirolimus-induced hypertriglyceridemia, it has been shown with an in vivo kinetic study that hypertriglyceridemia was mostly due to decreased very-LDL (VLDL) catabolism (56). In that study, treatment with sirolimus was associated with a 70% decrease in VLDL-apoB100 catabolism and a 28% decrease in IDL-apoB100 catabolism (56). In line with these kinetic results, a significant decrease in post-heparin lipoprotein lipase (LPL) activity (the major enzyme responsible for triglyceride catabolism) was observed in patients showing sirolimus-induced hypertriglyceridemia (56) (Fig.…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 99%

“…It has also been shown that in renal transplant patients, treatment with sirolimus induced a 42% increase in free fatty acid pool, suggesting an augmented release of free fatty acids from the adipose tissue that may be due to a reduction of the inhibition of the hormone-sensitive lipase by insulin (47). It has been postulated that this increase in free fatty acids may increase hepatic VLDL production, but such increase in VLDL production has not been clearly shown in human kinetic studies (56). As far as LDL cholesterol is concerned, a kinetic study performed in renal transplant patients has shown that treatment with sirolimus was associated with a 68% decrease in LDL-apoB100 catabolism (56).…”

Section: Effects Of Mtor Inhibitors On Lipids "mentioning

confidence: 99%

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ENDOCRINE SIDE EFFECTS OF ANTI-CANCER DRUGS: Effects of anti-cancer targeted therapies on lipid and glucose metabolism

Vergès

Walter

Cariou

2014

European Journal of Endocrinology

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During the past years, targeted therapies for cancer have been developed using drugs that have significant metabolic consequences. Among them, the mammalian target of rapamycin (mTOR) inhibitors and, to a much lesser extent, the tyrosine kinase inhibitors (TKIs) are involved. mTOR plays a key role in the regulation of cell growth as well as lipid and glucose metabolism. Treatment with mTOR inhibitors is associated with a significant increase in plasma triglycerides and LDL cholesterol. mTOR inhibitors seem to increase plasma triglycerides by reducing the activity of the lipoprotein lipase which is in charge of the catabolism of triglyceride-rich lipoproteins. The increase in LDL cholesterol observed with mTOR inhibitors seems to be due to a decrease in LDL catabolism secondary to a reduction of LDL receptor expression. In addition, treatment with mTOR inhibitors is associated with a high incidence of hyperglycemia, ranging from 13 to 50% in the clinical trials. The mechanisms responsible for hyperglycemia with new onset diabetes are not clear, but are likely due to the combination of impaired insulin secretion and insulin resistance. TKIs do not induce hyperlipidemia but alter glucose homeostasis. Treatment with TKIs may be associated either with hyperglycemia or hypoglycemia. The molecular mechanism by which TKIs control glucose homeostasis remains unknown. Owing to the metabolic consequences of these agents used as targeted anti-cancer therapies, a specific and personalized follow-up of blood glucose and lipids is recommended when using mTOR inhibitors and of blood glucose when using TKIs.

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Section: Effects Of Mtor Inhibitors On Lipids "supporting

confidence: 59%