Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences, Kitasato University, 5-9-1 Shirokane, Minato-ku, Tokyo 108-8641, Japan.
Arterioscler Thromb Vasc Biol. 2011 May;31(5):1108-15. doi: 10.1161/ATVBAHA.111.223552. Epub 2011 Mar 10.
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.
PPPA treatment (10 to 100 mg/kg) caused 30.5±4.7% to 55.8±3.3% 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 26.2±3.7% to 46±3.8% in the aortae and by 18.9±3.6% to 37.6±6.0% in the hearts.
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.
真菌来源的吡咯并吡喃酮 A（PPPA）是第一种被发现能在体外强烈且选择性地抑制酰基辅酶 A：胆固醇酰基转移酶 2（ACAT2）同工酶活性的化合物。本研究的目的是研究 ACAT2 选择性抑制剂在动脉粥样硬化中的体内疗效。
PPPA 治疗（10 至 100mg/kg）可使从小鼠肠道吸收的胆固醇抑制 30.5±4.7%至 55.8±3.3%。当 10 至 50mg/kg/天的 PPPA 口服给予载脂蛋白 E 基因敲除小鼠 12 周时，血浆胆固醇、极低密度脂蛋白（VLDL）和低密度脂蛋白（LDL）水平以及肝胆固醇含量降低。此外，VLDL 和 LDL 来源的胆固醇酯中胆甾醇油酸酯（仅在肝 ACAT2 中合成）与胆甾醇亚油酸酯的比例降低，表明 PPPA 抑制了肝 ACAT2 活性。用 PPPA 治疗的小鼠动脉粥样硬化病变面积减少，主动脉病变面积减少 26.2±3.7%至 46±3.8%，心脏病变面积减少 18.9±3.6%至 37.6±6.0%。
我们的研究结果表明，肠道和肝脏的 ACAT2 选择性抑制可有效对抗动脉粥样硬化，而 PPPA 似乎是一种有潜力的抗动脉粥样硬化先导化合物。本研究首次证明了 ACAT2 选择性抑制剂 PPPA 在动脉粥样硬化中的体内疗效。用 PPPA 治疗的动脉粥样硬化小鼠表现出肠道胆固醇吸收减少以及 LDL 和 VLDL 中胆固醇和胆甾醇油酸酯水平降低，从而保护了动脉粥样硬化的发展。
