title: Farnesoid X receptor induces murine scavenger receptor Class B type I via intron binding.
abstract: Farnesoid X receptor (FXR) is a nuclear receptor and a key regulator of liver cholesterol and triglyceride homeostasis. Scavenger receptor class B type I (SR-BI) is critical for reverse cholesterol transport (RCT) by transporting high-density lipoprotein (HDL) into liver. FXR induces SR-BI, however, the underlying molecular mechanism of this induction is not known. The current study confirmed induction of SR-BI mRNA by activated FXR in mouse livers, a human hepatoma cell line, and primary human hepatocytes. Genome-wide FXR binding analysis in mouse livers identified 4 putative FXR response elements in the form of inverse repeat separated by one nucleotide (IR1) at the first intron and 1 IR1 at the downstream of the mouse Sr-bi gene. ChIP-qPCR analysis revealed FXR binding to only the intronic IR1s, but not the downstream one. Luciferase assays and site-directed mutagenesis further showed that 3 out of 4 IR1s were able to activate gene transcription. A 16-week high-fat diet (HFD) feeding in mice increased hepatic Sr-bi gene expression in a FXR-dependent manner. In addition, FXR bound to the 3 bona fide IR1s in vivo, which was increased following HFD feeding. Serum total and HDL cholesterol levels were increased in FXR knockout mice fed the HFD, compared to wild-type mice. In conclusion, the Sr-bi/SR-BI gene is confirmed as a FXR target gene in both mice and humans, and at least in mice, induction of Sr-bi by FXR is via binding to intronic IR1s. This study suggests that FXR may serve as a promising molecular target for increasing reverse cholesterol transport.
authors.affiliation: Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America.
authors.forename: Guodong
authors.initials: G
authors.lastname: Li
authors.forename: Ann M
authors.initials: AM
authors.lastname: Thomas
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Williams
authors.forename: Bo
authors.initials: B
authors.lastname: Kong
authors.forename: Jie
authors.initials: J
authors.lastname: Liu
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Wen
authors.initials: W
authors.lastname: Xie
authors.forename: Grace L
authors.initials: GL
authors.lastname: Guo
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D059305:Diet, High-Fat; D005260:Female; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007438:Introns; D007555:Isoxazoles / Q000494:pharmacology; D008075:Lipoproteins, HDL / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051122:Scavenger Receptors, Class B / Q000235:genetics / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D002784:Cholesterol; D007555:Isoxazoles; D008075:Lipoproteins, HDL; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D051122:Scavenger Receptors, Class B; D000099150:Receptor, Farnesoid X-Activated; C412815:GW 4064