on September 13, 2007
Published online before print September 13, 2007, doi: 10.1161/ATVBAHA.107.147405
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Submitted on December 13, 2006
Accepted on August 19, 2007
Esculeogenin A, a New Tomato Sapogenol, Ameliorates Hyperlipidemia and Atherosclerosis in ApoE-Deficient Mice by Inhibiting ACAT
Yukio Fujiwara ;
From the Departments of Medical Biochemistry (Y.F., N.K., M.H., R.N.), and Cellular Pathology (M.T.), Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan the Department of Natural Medicine (Y.F., N.K., S.M., T.I., T.N.), Graduate School of Medical and Pharmaceutical Sciences, Kumamoto University, Kumamoto, Japan; and the Laboratory for Plant Biotechnology (Y.I., K.A., D.S.), Kazusa DNA Research Institute, Chiba, Japan.
* To whom correspondence should be addressed. E-mail: nagai-883{at}umin.ac.jp.
Objective—We recently identified esculeoside A, a new spirosolane-type glycoside, with a content in tomatoes that is 4-fold higher than that of lycopene. In the present study, we examined the effects of esculeoside A and esculeogenin A, a new aglycon of esculeoside A, on foam cell formation in vitro and atherogenesis in apoE-deficient mice.
Methods and Results—Esculeogenin A significantly inhibited the accumulation of cholesterol ester (CE) induced by acetylated low density lipoprotein (acetyl-LDL) in human monocyte-derived macrophages (HMDM) in a dose-dependent manner without inhibiting triglyceride accumulation, however, it did not inhibit the association of acetyl-LDL to the cells. Esculeogenin A also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-coenzymeA (CoA): cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that esculeogenin A suppresses the activity of both ACAT-1 and ACAT-2. Furthermore, esculeogenin A prevented the expression of ACAT-1 protein, whereas that of SR-A and SR-BI was not suppressed. Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol, triglycerides, LDL-cholesterol, and the areas of atherosclerotic lesions without any detectable side effects.
Conclusions—Our study provides the first evidence that purified esculeogenin A significantly suppresses the activity of ACAT protein and leads to reduction of atherogenesis.
Key words: esculeogenin A • atherosclerosis • ACAT • human monocyte-derived macrophages • foam cells
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