Molecular target of decursins in the inhibition of lipid droplet accumulation in macrophages.
During screening for inhibitors of lipid droplet accumulation in mouse peritoneal macrophages, two coumarins identified as decursin and decursinol angelate were isolated from the roots of Angelicae gigantis. The cellular molecular target of these inhibitors in macrophages was studied. Decursin and decursinol angelate inhibited cholesteryl ester (CE) synthesis with IC50 values of 9.7 and 10.1 microM, respectively, whereas they enhanced triacylglycerol (TG) synthesis. Lysosomal metabolism of cholesterol to CE was inhibited by the compounds, indicating that the site of inhibition is one of the steps between the exiting of cholesterol from the lysosomes and CE synthesis in the endoplasmic reticulum. Therefore, acyl-CoA:cholesterol acyltransferase (ACAT) activity in the microsomal fractions prepared from mouse macrophages was studied, and the results showed inhibition of this activity by decursin and decursinol angelate with IC50 values of 43 and 22 microM, respectively. Thus, it was concluded that the compounds inhibit macrophage ACAT activity to decrease CE synthesis, leading to a reduction of lipid droplets in macrophages.
Ohshiro
Taichi
T
Kitasato Institute for Life Sciences and Graduate School of Infection Control Sciences, Kitasato University, Tokyo, Japan.
Namatame
Ichiji
I
Lee
Eun Woo
EW
Kawagishi
Hirokazu
H
Tomoda
Hiroshi
H
D000818:Animals; D001578:Benzopyrans / Q000494:pharmacology*; D002087:Butyrates / Q000494:pharmacology*; D002788:Cholesterol Esters / Q000096:biosynthesis; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D050356:Lipid Metabolism / Q000187:drug effects*; D008099:Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism*; D051379:Mice; D018517:Plant Roots / Q000737:chemistry; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors
D001578:Benzopyrans; D002087:Butyrates; D002788:Cholesterol Esters; D004791:Enzyme Inhibitors; C101278:decursin; D002785:Sterol O-Acyltransferase