Abstract 19334: Pyripyropene A, a Selective Inhibitor of Acyl-CoA:cholesterol Acyltransferase 2, Attenuates Hypercholesterolemia and Atherosclerosis in Murine Models of Hyperlipidemia
Objective: Pyripyropene A (PPPA) is the first compound that has been found to strongly and selectively inhibit the acyl-CoA:cholesterol acyltransferase 2 (ACAT2) isozyme. The purpose of the present study was to investigate in vivo efficacy of the ACAT2-selective inhibitor in atherogenic mouse models.
Methods and Results: By a fecal dual isotope method method, PPPA treatment caused dose-dependent inhibition of the cholesterol absorption in mouse intestine (30.5±4.7 ∼ 55.8±3.3% inhibition at doses of 10 ∼ 100 mg/kg body weight). When PPPA (10, 25 and 50 mg/kg/day) was orally administered to apolipoprotein E knockout (Apoe−/−) mice for 12 weeks, plasma cholesterol levels as well as levels of very low density lipoproteins (VLDL) and low density lipoproteins (LDL) and hepatic cholesterol contents were dose-dependently lowered. Furthermore, the ratio of cholesteryl oleate (exclusively synthesized in hepatic ACAT2) to cholesteryl linolate in VLDL- and LDL-derived cholesteryl ester (CE) decreased in a dose-dependent fashion, indicating that hepatic ACAT2 activity was inhibited by PPPA. PPPA-treated mice reduced atherogenic lesion areas by 26.2±3.7, 36.2±4.9 and 46.5±3.8% in the aortae and 18.9±3.6, 30.0±5.9 and 37.6±6.0% in the hearts after 12-week PPPA treatment. During the experiments, no significant changes were observed on body weight, plasma glucose levels, alanine transaminase (ALT) activity and blood urea nitrogen (BUN) levels in PPPA-treated mice, indicating that PPPA treatment had no toxic effects on liver and kidney and no effect on glucose metabolism. Similarly, atherogenic lesion areas of LDL receptor knockout (Ldlr−/−) mice treated with PPPA (50 mg/kg/day) for 12 weeks was significantly reduced by 37.6±10.6% in the aortae and 51.4±10.8% in the hearts.
Conclusions: Our findings indicate that ACAT2-selective inhibition in the intestine and the liver by PPPA can be effective against atherosclerosis in mouse models and that PPPA appears to be a potential anti-atherogenic lead compound.
- © 2010 by American Heart Association, Inc.