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Aggarwal D, Fernandez ML, Soliman GA
Metabolism. 2006 Jun;55(6):794-802
Rapamycin, an mTOR inhibitor, disrupts triglyceride metabolism in
guinea pigs.
Department of Nutritional Sciences, University of Connecticut,
Storrs, CT 06269, USA.
This study was designed to define some of the
mechanisms by which rapamycin (RAPA), an mTOR inhibitor, induces
hypertriglyceridemia when used as an immunosuppressive or
antiproliferative agent and to determine whether low doses
result in less undesirable side effects. Thirty male guinea pigs
(n=10 per group) were randomly assigned to control (no RAPA),
low-RAPA (0.08 mg/d), or high-RAPA (0.85 mg/d) treatment for 3
weeks. Rapamycin treatment resulted in more than a 2-fold
increase in plasma triglycerides (TG) (P<.01), whereas no
differences were observed in plasma cholesterol between RAPA and
control groups. Low-RAPA treatment resulted in lower
concentrations of cholesterol in the aorta (28.6%) and lower
hepatic acyl-CoA cholesteryl acyltransferase activity compared
to control and high-RAPA groups (P<.01). In addition, acyl-CoA
cholesteryl acyltransferase activity was positively correlated
with aortic cholesterol (r=0.43, P<.05). In contrast, aortic TG
concentrations were higher in RAPA-treated guinea pigs than in
control (P<.01). Very low density lipoprotein and low-density
lipoprotein particles isolated from guinea pigs treated with
RAPA were larger in size and contained more TG molecules than
particles from control animals. Interestingly, plasma free fatty
acids and fasting plasma glucose were 65% and 72% higher in the
high-RAPA group than in control (P<.01). Tumor necrosis
factor-alpha concentrations in the aorta were 3.6- and 10.4-fold
higher in the low-RAPA and high-RAPA groups than in control
guinea pigs (P<.01). These results suggest that RAPA interferes
with TG metabolism by altering the insulin signaling pathway,
inducing increased secretion of very low density lipoprotein and
promoting deposition of TG in the aorta. Low RAPA was found to
decrease cholesterol accumulation in tissue (liver and aorta)
compared to high RAPA, suggesting that lower doses could be less
detrimental to transplant patients.
PMID: 16713440
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