Esculeogenin A, a new tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in ApoE-deficient mice by inhibiting ACAT.
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.


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.
Fujiwara
Yukio
Y
Department of Medical Biochemistry, Faculty of Medical and Pharmaceutical Sciences, Kumamoto University, Honjo, 1-1-1, Kumamoto 860-8556, Japan.
Kiyota
Naoko
N
Hori
Masaharu
M
Matsushita
Sayaka
S
Iijima
Yoko
Y
Aoki
Koh
K
Shibata
Daisuke
D
Takeya
Motohiro
M
Ikeda
Tsuyoshi
T
Nohara
Toshihiro
T
Nagai
Ryoji
R
D000818:Animals; D050197:Atherosclerosis / Q000188:drug therapy*; D016466:CHO Cells; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D004929:Esculin / Q000494:pharmacology*; D005487:Foam Cells / Q000187:drug effects*; D006801:Humans; D006937:Hypercholesterolemia / Q000188:drug therapy*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D010936:Plant Extracts / Q000494:pharmacology*; D012502:Sapogenins / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000187:drug effects*
D002788:Cholesterol Esters; D010936:Plant Extracts; D012502:Sapogenins; D004929:Esculin; D002785:Sterol O-Acyltransferase