Pyripyropene A

Acyl-CoA: cholesterol acyltransferase (ACAT) is a key enzyme for cholesteryl ester accumulation in atherogenesis, lipoprotein formation in liver, and cholesterol absorption from intestines, all of which are events that contribute to the atherosclerotic process. Two ACAT isozymes have been identified and are expressed in distinct tissues. ACAT1 is ubiquitously expressed at a high level in sebaceous glands, steroidogenic tissues, and macrophages, whereas ACAT2 is expressed predominantly in the liver and intestine. Pyripyropene A, naturally produced by A. fumigates, is a potent inhibitor of ACAT2 with an IC50 value of 70 nM in an in vitro activity assay. It demonstrates high selectivity for the ACAT2 isozyme, inhibiting ACAT1 in a similar assay with an IC50 value of > 80 μM.A dose of 10 to 100 mg/kg PPPA inhibits cholesterol absorption in mouse intestine by 30.5-55%. Oral administration to apolipoprotein E-knockout mice at 10-50 mg/kg per day for 12 weeks can lower the levels of plasma cholesterol and hepatic cholesterol, very-low-density lipoprotein, and LDL content, resulting in protection from atherosclerosis development.