Pyripyropene A, an Acyl–Coenzyme A:Cholesterol Acyltransferase 2–Selective Inhibitor, Attenuates Hypercholesterolemia and Atherosclerosis in Murine Models of Hyperlipidemia

Abstract

Objective-Pyripyropene A (PPPA) of fungal origin is the first compound that has been found to strongly and selectively inhibit acyl-coenzyme A:cholesterol acyltransferase 2 (ACAT2) isozyme activity in vitro. The purpose of the present study was to investigate in vivo efficacy of the ACAT2-selective inhibitor in atherosclerosis. Methods and Results-PPPA treatment (10 to 100 mg/kg) caused 30.5Ϯ4.7% to 55.8Ϯ3.3% inhibition of the cholesterol absorption from the mouse intestine. When PPPA (10 to 50 mg/kg per day) was orally administered to apolipoprotein E-knockout mice for 12 weeks, the levels of plasma cholesterol, very-low-density lipoprotein (VLDL), and low-density lipoprotein (LDL) and hepatic cholesterol content were lowered. Furthermore, the ratio of cholesteryl oleate (exclusively synthesized in hepatic ACAT2) to cholesteryl linoleate in VLDL-and LDL-derived cholesteryl ester decreased, indicating that hepatic ACAT2 activity was inhibited by PPPA. PPPA-treated mice had reduced atherogenic lesion areas that were lowered by 26.2Ϯ3.7% to 46Ϯ3.8% in the aortae and by 18.9Ϯ3.6% to 37.6Ϯ6.0% in the hearts. Conclusion-Our findings indicate that ACAT2-selective inhibition in the intestine and the liver can be effective against atherosclerosis and that PPPA appears to be a potential antiatherogenic lead compound. This study is the first demonstration of the in vivo efficacy of PPPA, an ACAT2-selective inhibitor, in atherosclerosis. PPPA-treated atherogenic mice showed a decrease in intestinal cholesterol absorption and cholesterol and cholesteryl oleate levels in both LDL and VLDL, resulting in protection of atherosclerosis development. Key Words: atherosclerosis Ⅲ hypercholesterolemia Ⅲ inhibitors C ardiovascular diseases are a group of disorders of the heart and blood vessels. They represent the leading cause of death globally, with more individuals dying each year from cardiovascular diseases than from any other cause. Statins, which are inhibitors of 3-hydroxy-3-methylglutarylcoenzyme A reductase, reduce the risk of complications and death from cardiovascular events by approximately 30%. 1 Consequently, the quest for novel pharmacological agents that target specific steps of atherogenesis has intensified significantly in recent years. The enzyme acyl-coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the synthesis of cholesteryl ester (CE) from free cholesterol and long-chain fatty acyl-coenzyme A, has been considered a promising therapeutic target. 2 Although a number of synthetic ACAT inhibitors have been developed, they have failed to reduce cardiovascular events in clinical trials.Two ACAT isozymes have been identified in mammals: ACAT1 and ACAT2. [3][4][5][6] Each isozyme has a distinct pattern of expression among tissues. Although ACAT1 is ubiquitously expressed at a high level in sebaceous glands, steroidogenic tissues, and macrophages, ACAT2 is expressed predominantly in the liver and intestine. 7 ACAT1-selective inhibition may cause detrimental effects, 8 -10 whereas ACAT2-selective inhibitio...

Absence of Nceh1 augments 25-hydroxycholesterol-induced ER stress and apoptosis in macrophages

“…K-604 ( 24 ) and CS-505 ( 25 ) were provided by Kowa Pharmaceutical, Daiichi Sankyo and Kyoto Pharmaceutical Industries, respectively. Pyripyropene A (PPPA) was purifi ed from a culture broth of the fungus, Aspergillus fumigatus FO-1289 ( 26,27 ). Cholesterol [1-…”

TG-interacting factor 1 acts as a transcriptional repressor of sterol O-acyltransferase 2

“…2E ) and protocols. Hepatic lipids were extracted as previously described ( 24,25 ). In brief, ‫ف‬ 100 mg liver was extracted in chloroformmethanol (2:1, v/v) and solubilized in 1% TritonX-100 solution, and total and free cholesterol and TGs were determined by enzymatic assays.…”

PRD125, a Potent and Selective Inhibitor of SterolO-Acyltransferase 2 Markedly Reduces Hepatic Cholesteryl Ester Accumulation and Improves Liver Function in Lysosomal Acid Lipase-Deficient Mice

“…The roles that both SOAT1 and SOAT2 play in generating cholesteryl esters, and therefore in the pathogenesis of atherosclerosis, have made these enzymes, particularly SOAT2, attractive targets for pharmacological intervention Rudel et al, 2005;Chang et al, 2006;Farese, 2006). This has led to the identification of a new group of compounds that are selective inhibitors of SOAT2 (Ohshiro et al, 2011;Ohtawa et al, 2013). Prior to the discovery that there are two sterol O-acyltransferases, decades of research into the development of various classes of SOAT inhibitors yielded a number of compounds that markedly suppressed cholesterol esterification in vitro and in animal models.…”