title: Fibrates down-regulate hepatic scavenger receptor class B type I protein expression in mice.
abstract: Fibrates are normolipidemic drugs used in atherogenic dyslipidemia because of their ability to raise high density lipoprotein (HDL) and decrease triglyceride levels. They exert multiple effects on lipid metabolism by activating the peroxisome proliferator-activated receptor-alpha (PPAR-alpha), which controls the transcriptional regulation of genes involved in hepatic fatty acid, cholesterol, and lipoprotein metabolism. The hepatic expression of the scavenger receptor class B type I (SR-BI) plays a critical role in lipoprotein metabolism, mainly due to its ability to mediate selective cholesterol uptake. Because fibrates and PPAR-alpha agonists up-regulate SR-BI expression in human and murine macrophages, we tested whether fibrates raised a similar regulatory response on hepatic SR-BI expression in mice. Surprisingly, fibrate treatment suppressed SR-BI protein expression in the liver without changing steady state SR-BI mRNA levels. Decreased hepatic SR-BI protein expression correlated with enlarged HDL particle size. This effect was concomitant with down-regulation of CLAMP, a putative SR-BI-stabilizing protein found in the hepatic plasma membrane, which was also not associated to changes in CLAMP mRNA levels. The post-transcriptional regulatory effect of fibrates over hepatic SR-BI protein levels was dependent on PPAR-alpha expression, because it was absent in PPAR-alpha-deficient mice. Restoring hepatic SR-BI expression in fibrate-treated mice by recombinant adenoviral gene transfer abolished fibrate-mediated HDL particle size enlargement. This study describes a novel effect of fibrates on hepatic SR-BI expression providing an alternative mechanism by which this drug family modulates HDL metabolism in vivo.
authors.affiliation: Departamento de Gastroenterologia, Facultad de Medicina, Pontificia Universidad Católica, Marcoleta 367, Santiago, Chile.
authors.forename: Pablo
authors.initials: P
authors.lastname: Mardones
authors.forename: Antoine
authors.initials: A
authors.lastname: Pilon
authors.forename: Muriel
authors.initials: M
authors.lastname: Bouly
authors.forename: Daniel
authors.initials: D
authors.lastname: Duran
authors.forename: Takako
authors.initials: T
authors.lastname: Nishimoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
authors.forename: Karen F
authors.initials: KF
authors.lastname: Kozarsky
authors.forename: Marcela
authors.initials: M
authors.lastname: Altayo
authors.forename: Juan Francisco
authors.initials: JF
authors.lastname: Miquel
authors.forename: Gerald
authors.initials: G
authors.lastname: Luc
authors.forename: Veronique
authors.initials: V
authors.lastname: Clavey
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Attilio
authors.initials: A
authors.lastname: Rigotti
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000187:drug effects*; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; D051122:Scavenger Receptors, Class B; D014162:Transfection
chemical_list: D018955:CD36 Antigens; D000960:Hypolipidemic Agents; D008565:Membrane Proteins; D012333:RNA, Messenger; D011971:Receptors, Immunologic; D018110:Receptors, Lipoprotein; D051116:Receptors, Scavenger; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B