Document Detail

A selective inhibitor of intestinal ACAT, EAB309 suppresses both intestinal and hepatic cholesterol output and stimulates chylomicron removal.
MedLine Citation:
PMID:  9763214     Owner:  NLM     Status:  MEDLINE    
The effect of a novel inhibitor of acylcoenzyme A:cholesterol acyltransferase (EC, ACAT), EAB309 (EAB) on plasma lipid metabolism was studied in cholesterol-fed rats. Orally administered EAB was not detected in the portal vein or the liver but distributed exclusively in the intestine, suggesting that this agent selectively inhibits intestinal ACAT. The rats were fed with either a cholesterol-diet or a cholesterol-diet containing 0.005% EAB (w/w) ad. libium for three weeks. ACAT activity in intestinal microsomes was significantly inhibited in EAB-treated rats. Hepatic ACAT activity was also decreased in EAB-treated rats, however, this was attenuated by the addition of excess cholesterol to the liver microsome, indicating that substrate availability is tightly associated with this enzyme's activity and the inhibition of hepatic ACAT by EAB is not direct. Incorporation of [3H]-cholesterol to cholesteryl ester (CE) in mesenteric lymph were markedly suppressed by EAB treatment. Chylomicrons (CMs) were doubly labeled with [3H]-vitamin A and [14C]-triglyceride (TG) in EAB-treated or non-treated rats and injected into normal chow-fed rats. The CMs from EAB-treated rats were cleared faster from the plasma and taken up more by the liver compared with the CMs from non-treated rats. The content of CE in newly secreted VLDL was remarkably decreased by EAB treatment without affecting TG output. These results demonstrate that EAB, a novel inhibitor of intestinal ACAT, significantly suppresses both intestinal and hepatic CE output and stimulates CM removal. This suggests that the inhibition of intestinal ACAT can subsequently suppress hepatic ACAT by decreased CE delivery from the intestine to the liver.
Y Umeda; T Hirano; Y Kako; K Kamagata; K Okuyama; K Suzuki
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Life sciences     Volume:  63     ISSN:  0024-3205     ISO Abbreviation:  Life Sci.     Publication Date:  1998  
Date Detail:
Created Date:  1998-10-15     Completed Date:  1998-10-15     Revised Date:  2003-11-14    
Medline Journal Info:
Nlm Unique ID:  0375521     Medline TA:  Life Sci     Country:  ENGLAND    
Other Details:
Languages:  eng     Pagination:  PL187-95     Citation Subset:  IM    
Department of Pediatrics, Showa University School of Medicine, Tokyo, Japan.
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MeSH Terms
Cholesterol / administration & dosage,  biosynthesis,  blood*
Chylomicrons / drug effects,  metabolism*
Dioxoles / pharmacology*
Enzyme Inhibitors / pharmacology*
Intestines / drug effects*,  metabolism*
Lipoproteins, VLDL / biosynthesis
Liver / drug effects*,  enzymology,  metabolism*
Lymph Nodes / metabolism
Phenylurea Compounds / pharmacology*
Rats, Wistar
Sterol O-Acyltransferase / antagonists & inhibitors*
Triglycerides / biosynthesis,  blood
Reg. No./Substance:
0/Chylomicrons; 0/Dioxoles; 0/EAB 309; 0/Enzyme Inhibitors; 0/Lipoproteins, VLDL; 0/Phenylurea Compounds; 0/Triglycerides; 57-88-5/Cholesterol; EC O-Acyltransferase

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