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: Christian Lemieux, Yves Gélinas, Josée Lalonde, Fernand Labrie, Denis Richard, Yves Deshaies
• Journal: Metabolism: clinical and experimental (Metabolism) Vol. 55 Issue 5 Pg. 605-13 (May 2006) ISSN: 0026-0495 [Print] United States
• PMID: 16631436 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP-Binding Cassette Transporters
• Blood Glucose
• Cholesterol, Dietary
• Piperidines
• RNA, Messenger
• Receptors, LDL
• Selective Estrogen Receptor Modulators
• Sterol Regulatory Element Binding Proteins
• ritetronium
• Hydroxymethylglutaryl CoA Reductases

Topics

• ATP-Binding Cassette Transporters (genetics, metabolism)
• Animals
• Blood Glucose (metabolism)
• Cholesterol, Dietary (metabolism)
• Female
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Hypercholesterolemia (drug therapy, metabolism)
• Liver (metabolism)
• Ovariectomy
• Piperidines (pharmacology)
• RNA, Messenger (chemistry, genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, LDL (metabolism)
• Reverse Transcriptase Polymerase Chain Reaction
• Selective Estrogen Receptor Modulators (pharmacology)
• Statistics, Nonparametric
• Sterol Regulatory Element Binding Proteins (genetics, metabolism)
• Weight Gain