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 30.5±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.

CONCLUSIONS:

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.

• Authors: Taichi Ohshiro, Daisuke Matsuda, Kent Sakai, Chiara Degirolamo, Hiroaki Yagyu, Lawrence L Rudel, Satoshi Omura, Shun Ishibashi, Hiroshi Tomoda
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 31 Issue 5 Pg. 1108-15 (May 2011) ISSN: 1524-4636 [Electronic] United States
• PMID: 21393580 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anticholesteremic Agents
• Apolipoproteins E
• Cholesterol Esters
• Cholesterol, Dietary
• Enzyme Inhibitors
• Lipoproteins, LDL
• Lipoproteins, VLDL
• Pyridines
• Sesquiterpenes
• pyripyropene A
• cholesteryl oleate
• cholesteryl linoleate
• Sterol O-Acyltransferase
• sterol O-acyltransferase 2

Topics

• Analysis of Variance
• Animals
• Anticholesteremic Agents (pharmacology)
• Apolipoproteins E (deficiency, genetics)
• Atherosclerosis (enzymology, genetics, pathology, prevention & control)
• Cholesterol Esters (metabolism)
• Cholesterol, Dietary (blood)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Enzyme Inhibitors (pharmacology)
• Hypercholesterolemia (enzymology, genetics, pathology, prevention & control)
• Intestinal Absorption (drug effects)
• Intestines (drug effects, enzymology)
• Lipoproteins, LDL (blood)
• Lipoproteins, VLDL (blood)
• Liver (drug effects, enzymology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Pyridines (pharmacology)
• Sesquiterpenes (pharmacology)
• Sterol O-Acyltransferase (antagonists & inhibitors, metabolism)
• Time Factors