title: Hypocholesterolemic action of the selective estrogen receptor modulator acolbifene in intact and ovariectomized rats with diet-induced hypercholesterolemia.
abstract: Acolbifene (ACOL) is a fourth-generation selective estrogen receptor modulator (SERM) that has strong and pure antiestrogenic properties toward estrogen-sensitive cancers, but improves energy and lipid metabolism in an estrogen-like fashion in rodent models. The aim of this study was to determine the potency of ACOL to reduce cholesterolemia in a dietary model of hypercholesterolemia and to establish its mechanisms of action. Intact and ovariectomized (OVX) female rats were treated for 3 weeks with ACOL, and serum cholesterol and liver determinants of cholesterol metabolism were assessed. Acolbifene prevented both diet- and ovariectomy-induced weight gain and completely prevented diet-induced hypercholesterolemia. Relative to a reference chow diet, the high-cholesterol diet decreased the high-density lipoprotein (HDL) cholesterol fraction, which remained unaffected by ACOL, indicating that in hypercholesterolemic conditions, ACOL modulated only the non-HDL fraction. No impact of ACOL on determinants of liver cholesterol synthesis was observed. In contrast, ACOL increased hepatic low-density lipoprotein receptor protein in both intact and OVX rats, which was negatively correlated with serum total and non-HDL cholesterol (r=-0.59, P<.0001), suggesting a contribution of receptor-mediated hepatic uptake of cholesterol-rich lipoproteins to the hypocholesterolemic effect of ACOL. These findings establish that ACOL retains its powerful cholesterol-lowering action in diet-induced hypercholesterolemia and suggest that the SERM acts in such conditions through favoring hepatic low-density lipoprotein receptor-mediated uptake of cholesterol transported by non-HDL lipoprotein fractions.
authors.affiliation: Laval Hospital Research Center, Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada G1K 7P4.
authors.forename: Christian
authors.initials: C
authors.lastname: Lemieux
authors.forename: Yves
authors.initials: Y
authors.lastname: Gélinas
authors.forename: Josée
authors.initials: J
authors.lastname: Lalonde
authors.forename: Fernand
authors.initials: F
authors.lastname: Labrie
authors.forename: Denis
authors.initials: D
authors.lastname: Richard
authors.forename: Yves
authors.initials: Y
authors.lastname: Deshaies
mesh_terms: D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002791:Cholesterol, Dietary / Q000378:metabolism; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D006937:Hypercholesterolemia / Q000188:drug therapy* / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D011973:Receptors, LDL / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D018709:Statistics, Nonparametric; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism; D015430:Weight Gain
chemical_list: D018528:ATP-Binding Cassette Transporters; D001786:Blood Glucose; D002791:Cholesterol, Dietary; D010880:Piperidines; D012333:RNA, Messenger; D011973:Receptors, LDL; D020845:Selective Estrogen Receptor Modulators; D051779:Sterol Regulatory Element Binding Proteins; C012121:ritetronium; D006903:Hydroxymethylglutaryl CoA Reductases