The molecular target of rubimaillin in the inhibition of lipid droplet accumulation in macrophages.
The naphthohydroquinone rubimaillin, which has an angular-type three cyclic skeleton and was isolated from the Chinese medical plant Rubia cordifola, was found to inhibit lipid droplet accumulation in mouse macrophages and to selectively inhibit cholesteryl ester synthesis (IC(50): 18 microM). The metabolism of cholesterol from lysosomes to lipid droplets was inhibited by the compound with a similar IC(50) (45 microM). Moreover, rubimaillin inhibited acyl-CoA:cholesterol acyltransferase (ACAT1) activity in ACAT1-expressing cells (IC(50): 80 microM). Thus, these data strongly suggest that rubimaillin inhibits macrophage ACAT activity in order to decrease cholesteryl ester (CE) synthesis, leading to a reduction in the number of lipid droplets. Furthermore, rubimaillin was found to inhibit the ACAT2 isozyme in ACAT2-expressing cells (IC(50): 22 microM). We concluded that rubimaillin is a dual inhibitor of ACAT1 and ACAT2, but is more selective for the ACAT2 isozyme.
Matsuda
Daisuke
D
Graduate School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
Ohshiro
Taichi
T
Ohba
Mio
M
Jiang
Wei
W
Hong
Bin
B
Si
Shuyi
S
Tomoda
Hiroshi
H
D000818:Animals; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D002788:Cholesterol Esters / Q000096:biosynthesis; D006224:Cricetinae; D003412:Cricetulus; D003600:Cytosol / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004365:Drugs, Chinese Herbal / Q000737:chemistry / Q000494:pharmacology*; D007527:Isoenzymes; D050356:Lipid Metabolism / Q000187:drug effects*; D017737:Macrophages, Peritoneal / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors; D014162:Transfection; D000097587:Sterol O-Acyltransferase 2
D002784:Cholesterol; D002788:Cholesterol Esters; D004365:Drugs, Chinese Herbal; D007527:Isoenzymes; D011714:Pyrans; D002785:Sterol O-Acyltransferase; D000097587:Sterol O-Acyltransferase 2; C046245:rubimaillin; C493492:sterol O-acyltransferase 1