title: ACAT inhibition decreases LDL cholesterol in rabbits fed a cholesterol-free diet. Marked changes in LDL cholesterol without changes in LDL receptor mRNA abundance.
abstract: Rabbits fed low-fat, cholesterol-free diets containing casein as the sole protein source develop endogenous hypercholesterolemia (EH). To test the hypothesis that lipoprotein cholesteryl esters in EH rabbits are acyl coenzyme A:cholesterol acyltransferase (ACAT) derived, we treated EH rabbits with CI-976, a potent and selective ACAT inhibitor. In addition, since cholesterol and bile acid synthesis as well as low-density lipoprotein (LDL) receptor activity are reduced in EH rabbits, we determined whether changes in gene expression for 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, 7 alpha-hydroxylase, and the LDL receptor might be associated with the efficacy due to ACAT inhibition. Compared with EH controls, CI-976-treated rabbits (50 mg/kg per day for 5 weeks) had decreased plasma total cholesterol (-43%), very-low-density lipoprotein (VLDL) cholesterol (-62%), LDL cholesterol (-43%), plasma apolipoprotein B (-23%), liver cholesteryl esters (-39%), LDL size, VLDL and LDL cholesteryl ester content (percent of total lipids), cholesteryl oleate/cholesteryl linoleate ratios in VLDL and LDL (25% to 30%), and ex vivo liver ACAT activity. The triglyceride/cholesteryl ester ratio increased twofold to fourfold in these apolipoprotein B-containing lipoproteins. Endogenous cholesterol absorption appeared to be unaffected by drug treatment. CI-976 failed to alter specific hepatic mRNAs involved in cholesterol metabolism, but comparisons among dietary control groups revealed a marked reduction in 7 alpha-hydroxylase mRNA, no change in LDL receptor mRNA, and an increase in HMG-CoA reductase mRNA in EH rabbits compared with normal chow-fed controls.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Department of Atherosclerosis Therapeutics, Parke-Davis Research Division of Warner Lambert Co, Ann Arbor, MI 48105.
authors.forename: B R
authors.initials: BR
authors.lastname: Krause
authors.forename: M E
authors.initials: ME
authors.lastname: Pape
authors.forename: K
authors.initials: K
authors.lastname: Kieft
authors.forename: B
authors.initials: B
authors.lastname: Auerbach
authors.forename: C L
authors.initials: CL
authors.lastname: Bisgaier
authors.forename: R
authors.initials: R
authors.lastname: Homan
authors.forename: R S
authors.initials: RS
authors.lastname: Newton
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases; D002784:Cholesterol / Q000008:administration & dosage*; D008078:Cholesterol, LDL / Q000097:blood*; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics; D004041:Dietary Fats / Q000008:administration & dosage*; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000378:metabolism; D008297:Male; D012333:RNA, Messenger / Q000378:metabolism*; D011817:Rabbits; D011973:Receptors, LDL / Q000235:genetics; D013250:Steroid Hydroxylases / Q000235:genetics; D002785:Sterol O-Acyltransferase / Q000037:antagonists & inhibitors*
chemical_list: D000813:Anilides; D008078:Cholesterol, LDL; D004041:Dietary Fats; D012333:RNA, Messenger; D011973:Receptors, LDL; C069304:PD 128042; D003577:Cytochrome P-450 Enzyme System; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C029009:steroid hormone 7-alpha-hydroxylase; D002785:Sterol O-Acyltransferase