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

DOI Web Site PubMed 被引用文献24件 参考文献41件 オープンアクセス
  • Taichi Ohshiro
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Daisuke Matsuda
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Kent Sakai
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Chiara Degirolamo
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Hiroaki Yagyu
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Lawrence L. Rudel
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Satoshi Ōmura
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Shun Ishibashi
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).
  • Hiroshi Tomoda
    From the Department of Microbial Chemistry, Graduate School of Pharmaceutical Sciences (T.O., D.M., K.S., H.T.) and Kitasato Institute for Life Sciences (S.Ō.), Kitasato University, Minato-Ku, Tokyo, Tokyo, Japan; Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Shimotsuke, Tochigi, Japan (T.O., H.Y., S.I.); Lipid Sciences Section, Department of Pathology, Wake Forest University School of Medicine, Winston-Salem, NC (C.D., L.L.R.).

説明

<jats:sec> <jats:title>Objective—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Methods and Results—</jats:title> <jats:p>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.</jats:p> </jats:sec> <jats:sec> <jats:title>Conclusion—</jats:title> <jats:p>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.</jats:p> </jats:sec>

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