20
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Genome-Wide Binding and Transcriptome Analysis of Human Farnesoid X Receptor in Primary Human Hepatocytes

      research-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Background & Aims

          Farnesoid X receptor (FXR, NR1H4) is a ligand-activated transcription factor, belonging to the nuclear receptor superfamily. FXR is highly expressed in the liver and is essential in regulating bile acid homeostasis. FXR deficiency is implicated in numerous liver diseases and mice with modulation of FXR have been used as animal models to study liver physiology and pathology. We have reported genome-wide binding of FXR in mice by chromatin immunoprecipitation - deep sequencing (ChIP-seq), with results indicating that FXR may be involved in regulating diverse pathways in liver. However, limited information exists for the functions of human FXR and the suitability of using murine models to study human FXR functions.

          Methods

          In the current study, we performed ChIP-seq in primary human hepatocytes (PHHs) treated with a synthetic FXR agonist, GW4064 or DMSO control. In parallel, RNA deep sequencing (RNA-seq) and RNA microarray were performed for GW4064 or control treated PHHs and wild type mouse livers, respectively.

          Results

          ChIP-seq showed similar profiles of genome-wide FXR binding in humans and mice in terms of motif analysis and pathway prediction. However, RNA-seq and microarray showed more different transcriptome profiles between PHHs and mouse livers upon GW4064 treatment.

          Conclusions

          In summary, we have established genome-wide human FXR binding and transcriptome profiles. These results will aid in determining the human FXR functions, as well as judging to what level the mouse models could be used to study human FXR functions.

          Related collections

          Most cited references24

          • Record: found
          • Abstract: found
          • Article: not found

          Identification of a nuclear receptor for bile acids.

          Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor. When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter. These results demonstrate a mechanism by which bile acids transcriptionally regulate their biosynthesis and enterohepatic transport.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis.

            Bile acids repress the transcription of cytochrome P450 7A1 (CYP7A1), which catalyzes the rate-limiting step in bile acid biosynthesis. Although bile acids activate the farnesoid X receptor (FXR), the mechanism underlying bile acid-mediated repression of CYP7A1 remained unclear. We have used a potent, nonsteroidal FXR ligand to show that FXR induces expression of small heterodimer partner 1 (SHP-1), an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP-1 represses expression of CYP7A1 by inhibiting the activity of liver receptor homolog 1 (LRH-1), an orphan nuclear receptor that is known to regulate CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Targeted disruption of the nuclear receptor FXR/BAR impairs bile acid and lipid homeostasis.

              Mice lacking the nuclear bile acid receptor FXR/BAR developed normally and were outwardly identical to wild-type littermates. FXR/BAR null mice were distinguished from wild-type mice by elevated serum bile acid, cholesterol, and triglycerides, increased hepatic cholesterol and triglycerides, and a proatherogenic serum lipoprotein profile. FXR/BAR null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein. Bile acid repression and induction of cholesterol 7alpha-hydroxylase and the ileal bile acid binding protein, respectively, did not occur in FXR/BAR null mice, establishing the regulatory role of FXR/BAR for the expression of these genes in vivo. These data demonstrate that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
                Bookmark

                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                8 September 2014
                : 9
                : 9
                : e105930
                Affiliations
                [1 ]Department of Pharmacology and Toxicology, School of Pharmacy, Rutgers University, Piscataway, New Jersey, United States of America
                [2 ]Department of Pharmacology, Toxicology, and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas, United States of America
                [3 ]Department of Medical Pathology and Laboratory Medicine, University of California, Davis Health Systems, Sacramento, California, United States of America
                [4 ]College of Science, Institute for Computer Applications, Huazhong Agricultural University, Wuhan, Hubei, China
                [5 ]Department of Pharmaceutical Sciences, School of Pharmacy, University of Connecticut, Storrs, Connecticut, United States of America
                [6 ]Biometric Research Branch, National Cancer Institute, Rockville, Maryland, United States of America
                IRCCS Istituto Oncologico Giovanni Paolo II, Italy
                Author notes

                Competing Interests: The authors have declared that no competing interest exist.

                Conceived and designed the experiments: GLG LZ. Performed the experiments: LZ HXL BK. Analyzed the data: LZ GLG YF BK YH. Contributed reagents/materials/analysis tools: GLG YYW JF XZ. Contributed to the writing of the manuscript: LZ GLG BK.

                Article
                PONE-D-14-20297
                10.1371/journal.pone.0105930
                4157742
                25198545
                c26d3045-686c-4983-8ba7-5bacf6e4e942
                Copyright @ 2014

                This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 9 May 2014
                : 20 July 2014
                Page count
                Pages: 10
                Funding
                This study was supported by the NIH fund, grants DK081343, DK090036 and GM104037. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology and life sciences
                Computational Biology
                Genome Analysis
                Gene Ontologies
                Gene Ontology Annotations
                Gene Ontology Associations
                Chromatin Immunoprecipitation
                Molecular biology
                Molecular biology techniques
                Sequencing techniques
                Sequence Analysis
                Sequence Motif Analysis
                High throughput sequencing
                RNA sequencing
                Physiology
                Medicine and Health Sciences
                Gastroenterology and Hepatology
                Liver Diseases
                Custom metadata
                The authors confirm that, for approved reasons, some access restrictions apply to the data underlying the findings. All sequencing data files were stored in the NCBI GEO database ( http://www.ncbi.nlm.nih.gov/geo/) with accession code GSE57312. The datasets will be made available to public upon manuscript acceptance. http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irylcwywtrgxhmt&acc=GSE57312

                Uncategorized
                Uncategorized

                Comments

                Comment on this article