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Papers In Press, published online ahead of print March 1, 2005
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Anatomy & Physiology, Laval University, Faculty of Medicine, Quebec, Quebec G1K 7P4
Corresponding Author: yves.deshaies{at}phs.ulaval.ca
This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) Acolbifene (ACOL). Rats were treated for 4 weeks with ACOL, fasted for 12 h and studied before and up to 6 h after refeeding. Plasma triglycerides (TG) were lowered by ACOL in both the fasting and fed states, an effect that was associated with a lower VLDL-TG secretion rate (–25%) and decreased mRNA of microsomal triglyceride transfer protein (–29%). An ACOL-induced increase in liver TG concentration (+100%) was accompanied by an amplification of the refeeding-induced elevation in the master lipogenic regulators sterol regulatory element binding proteins (SREBP)-1a and –1c. ACOL lowered total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and hydroxymethylglutaryl coenzyme A reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor, class B, type 1 (SR-B1) protein, but not mRNA, was 3-fold higher in ACOL-treated than in control animals, and correlated with plasma HDL-CHOL levels (r=0.80, P<0.002). Refeeding increased SR-B1 protein in untreated rats only, to levels found in ACOL-treated rats. Liver LDL receptor protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. The study demonstrates that ACOL possesses the unique ability among SERM to reduce VLDL-TG secretion, likely via reducing MTP expression. The findings also strongly suggest that the robust hypocholesterolemic action of ACOL may at least partly be due to increased removal of CHOL from the circulation consequent to enhanced liver SR-B1 and LDL receptor abundance.
Revised on February 17, 2005
Accepted on February 28, 2005
The hypolipidemic action of the selective estrogen receptor modulator Acolbifene is associated with decreased liver MTP and increased SR-B1 and LDL receptors
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