Tomatidine, a tomato sapogenol, ameliorates hyperlipidemia and atherosclerosis in apoE-deficient mice by inhibiting acyl-CoA:cholesterol acyl-transferase (ACAT).
It was previously revealed that esculeoside A, a new glycoalkaloid, and esculeogenin A, a new aglycon of esculeoside A, contained in ripe tomato ameliorate atherosclerosis in apoE-deficent mice. This study examined whether tomatidine, the aglycone of tomatine, which is a major tomato glycoalkaloid, also shows similar inhibitory effects on cholesterol ester (CE) accumulation in human monocyte-derived macrophages (HMDM) and atherogenesis in apoE-deficient mice. Tomatidine significantly inhibited the CE accumulation induced by acetylated LDL in HMDM in a dose-dependent manner. Tomatidine also inhibited CE formation in Chinese hamster ovary cells overexpressing acyl-CoA:cholesterol acyl-transferase (ACAT)-1 or ACAT-2, suggesting that tomatidine suppresses both ACAT-1 and ACAT-2 activities. Furthermore, the oral administration of tomatidine to apoE-deficient mice significantly reduced levels of serum cholesterol, LDL-cholesterol, and areas of atherosclerotic lesions. The study provides the first evidence that tomatidine significantly suppresses the activity of ACAT and leads to reduction of atherogenesis.
Department of Cell Pathology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
Yukio
Y
Fujiwara
Naoko
N
Kiyota
Keiichiro
K
Tsurushima
Makiko
M
Yoshitomi
Hasita
H
Horlad
Tsuyoshi
T
Ikeda
Toshihiro
T
Nohara
Motohiro
M
Takeya
Ryoji
R
Nagai
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002788:Cholesterol Esters / Q000378:metabolism; D006224:Cricetinae; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D018551:Solanum lycopersicum / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010936:Plant Extracts / Q000008:administration & dosage*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014053:Tomatine / Q000008:administration & dosage / Q000031:analogs & derivatives*
D001057:Apolipoproteins E; D002788:Cholesterol Esters; D010936:Plant Extracts; C003677:tomatidine; D014053:Tomatine; D002785:Sterol O-Acyltransferase