Distinct mechanisms by which low and high rapamycin doses raise plasma triglycerides in guinea pigs

To define the mechanisms by which rapamycin (RAPA), an mTOR inhibitor, induces hypertriglyceridemia and to determine if low doses result in less undesirable side effects, thirty male guinea pigs (10/ group) were randomly assigned to control (no RAPA), low‐RAPA (1.8mg) or high‐RAPA (18mg) for three weeks. Plasma triglycerides (TG) values increased from 24.5 ± 5.9 (control) to 55.2 ± 31.0 (low‐RAPA) and 56.9 ± 29.9mg/dL (high‐RAPA) (P < 0.01), with no differences in plasma cholesterol between the groups. Low RAPA treatment resulted in lower values of cholesterol in the aorta (28.6%) and lower hepatic ACAT activity compared to the other two groups (P < 0.01). ACAT activity was positively correlated with aortic cholesterol (r =0.43, P < 0.05). Aortic TG concentrations were higher in RAPA‐ treated guinea pigs compared to control (P < 0.01). VLDL and LDL particles were larger in size and contained more TG molecules in RAPA groups than particles from control animals. Plasma free fatty acids increased significantly from 0.47 ± 0.13 (control) to 0.64 ± 0.13(low‐RAPA) and 0.78 ± 0.30mEq/L (high‐RAPA) and fasting plasma glucose were higher in the high‐RAPA group than the control (255+53 VS 148+38 mg/dL) (P < 0.01). Tumor necrosis alpha factor concentrations in the aorta were higher in RAPA groups (P <0.01). Results suggest that RAPA interferes with TG metabolism by altering the insulin signaling pathway, inducing increased secretion of VLDL and promoting deposition of TG in the aorta. Low‐RAPA was found to decrease cholesterol accumulation in liver and aorta suggesting that lower doses if efficacious would be more beneficial [Supported by NIH‐KO1‐DK60654 award to GS]