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Farnesoid x receptor induces murine scavenger receptor class B type I via intron binding

Li, G and Thomas, AM and Williams, JA and Kong, B and Liu, J and Inaba, Y and Xie, W and Guo, GL (2012) Farnesoid x receptor induces murine scavenger receptor class B type I via intron binding. PLoS ONE, 7 (4).

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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. © 2012 Li et al.

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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Li, G
Thomas, AM
Williams, JA
Kong, B
Liu, J
Inaba, Y
Xie, Wwex6@pitt.eduWEX6
Guo, GL
Contributors:
ContributionContributors NameEmailPitt UsernameORCID
EditorMoschetta, AntonioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Date: 23 April 2012
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 7
Number: 4
DOI or Unique Handle: 10.1371/journal.pone.0035895
Schools and Programs: School of Pharmacy > Pharmaceutical Sciences
Refereed: Yes
MeSH Headings: Animals; Base Sequence; Cells, Cultured; Cholesterol--metabolism; Diet, High-Fat; Female; Hep G2 Cells; Hepatocytes--drug effects; Hepatocytes--metabolism; Humans; Introns; Isoxazoles--pharmacology; Lipoproteins, HDL--metabolism; Liver--drug effects; Liver--metabolism; Mice; Mice, Inbred C57BL; Molecular Sequence Data; Mutagenesis, Site-Directed; RNA, Messenger--metabolism; Receptors, Cytoplasmic and Nuclear--deficiency; Receptors, Cytoplasmic and Nuclear--genetics; Receptors, Cytoplasmic and Nuclear--metabolism; Scavenger Receptors, Class B--genetics; Scavenger Receptors, Class B--metabolism
Other ID: NLM PMC3335076
PubMed Central ID: PMC3335076
PubMed ID: 22540009
Date Deposited: 24 Sep 2012 20:26
Last Modified: 29 Jan 2019 15:55
URI: http://d-scholarship.pitt.edu/id/eprint/14174

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