Hypolipidemic action of the SERM acolbifene is associated with decreased liver MTP and increased SR-BI and LDL receptors.
This study aimed to identify the mechanisms of the hypolipidemic action of the selective estrogen receptor modulator (SERM) acolbifene (ACOL). Four weeks of treatment with ACOL reduced fasting and postprandial plasma triglycerides (TGs), an effect associated with lower VLDL-TG secretion rate (-25%), and decreased mRNA of microsomal triglyceride transfer protein (MTP; -29%). ACOL increased liver TG concentration (+100%) and amplified the feeding-induced increase in the master lipogenic regulators sterol-regulatory element binding protein-1a (SREBP-1a) and SREBP-1c. ACOL decreased total, HDL, and non-HDL cholesterol (CHOL) by 50%. SREBP-2 mRNA and HMG-CoA reductase activity were minimally affected by ACOL. However, in the fasted state, liver concentration of scavenger receptor class B type I (SR-BI) 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). Liver LDL receptor (LDLR) protein, but not mRNA, was increased 2-fold by ACOL, independently of the nutritional status. This study demonstrates that ACOL possesses the unique ability among SERMs to reduce VLDL-TG secretion, likely by reducing MTP expression, and strongly suggests that the robust hypocholesterolemic action of ACOL is related to increased removal of CHOL from the circulation as a consequence of enhanced liver SR-BI and LDLR abundance.
Lemieux
Christian
C
Laval Hospital Research Center, Department of Anatomy and Physiology, Faculty of Medicine, Laval University, Quebec City, Quebec, Canada G1K 7P4.
Gélinas
Yves
Y
Lalonde
Josée
J
Labrie
Fernand
F
Cianflone
Katherine
K
Deshaies
Yves
Y
D000818:Animals; D015153:Blotting, Western; D022762:CCAAT-Enhancer-Binding Proteins / Q000378:metabolism; D018955:CD36 Antigens; D002352:Carrier Proteins / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D005260:Female; D005508:Food Deprivation; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D007700:Kinetics; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011971:Receptors, Immunologic / Q000378:metabolism; D011973:Receptors, LDL / Q000378:metabolism; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology*; D051780:Sterol Regulatory Element Binding Protein 1; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D014280:Triglycerides / Q000097:blood
D022762:CCAAT-Enhancer-Binding Proteins; D018955:CD36 Antigens; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D047493:PPAR alpha; D010880:Piperidines; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D011973:Receptors, LDL; D051116:Receptors, Scavenger; C495125:Scarb1 protein, rat; D051122:Scavenger Receptors, Class B; D020845:Selective Estrogen Receptor Modulators; C497389:Srebf1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D014157:Transcription Factors; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C012121:ritetronium; D002784:Cholesterol; D006903:Hydroxymethylglutaryl CoA Reductases