This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/11/2400    most recent ATVBAHA.107.147405v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujiwara, Y. Articles by Nagai, R. Search for Related Content PubMed PubMed Citation Articles by Fujiwara, Y. Articles by Nagai, R.

(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:2400.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Esculeogenin A, a New Tomato Sapogenol, Ameliorates Hyperlipidemia and Atherosclerosis in ApoE-Deficient Mice by Inhibiting ACAT

Yukio Fujiwara; Naoko Kiyota; Masaharu Hori; Sayaka Matsushita; Yoko Iijima; Koh Aoki; Daisuke Shibata; Motohiro Takeya; Tsuyoshi Ikeda; Toshihiro Nohara; Ryoji Nagai

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.

Correspondence to Dr Ryoji Nagai, PhD, Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Honjo, 1-1-1, Kumamoto 860-8556, Japan. 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.

Esculeogenin A, a new aglycon of esculeoside A isolated from tomato, significantly inhibited the accumulation of cholesterol ester in macrophages by inhibiting acyl-CoA: cholesterol acyl-transferase (ACAT). Oral administration of esculeoside A to apoE-deficient mice significantly reduced the levels of serum cholesterol and the areas of atherosclerotic lesions.

Key Words: esculeogenin A • atherosclerosis • ACAT • human monocyte-derived macrophages • foam cells

This article has been cited by other articles:

				K. Taketa, T. Matsumura, M. Yano, N. Ishii, T. Senokuchi, H. Motoshima, Y. Murata, S. Kim-Mitsuyama, T. Kawada, H. Itabe, et al. Oxidized Low Density Lipoprotein Activates Peroxisome Proliferator-activated Receptor-{alpha} (PPAR{alpha}) and PPAR{gamma} through MAPK-dependent COX-2 Expression in Macrophages J. Biol. Chem., April 11, 2008; 283(15): 9852 - 9862. [Abstract] [Full Text] [PDF]