ArticlePloS one2014
Human FXR regulates SHP expression through direct binding to an LRH-1 binding site, independent of an IR-1 and LRH-1.
Article in PloS one, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 42 citations in OpenAlex.
- FXR in bone metabolism: An emerging regulator.iScience · 2026Review
- Transcriptional regulation of ubiquitin specific peptidase 2b by farnesoid X receptor and its implications in the pathogenesis of hepatocellular carcinoma.American journal of cancer research · 2026Article
- The roles of nuclear receptors in cholesterol metabolism and reverse cholesterol transport in nonalcoholic fatty liver disease.Hepatology communications · 2024Review
- FXR Friend-ChIPs in the Enterohepatic System.Seminars in liver disease · 2023Review
- Pathogenic mechanisms and regulatory factors involved in alcoholic liver disease.Journal of translational medicine · 2023Review
- Bile Acids Induce Neurite Outgrowth in Nsc-34 Cells via TGR5 and a Distinct Transcriptional Profile.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure.Toxicology and applied pharmacology · 2022Article
- Structural and Functional Analysis of SHP Promoter and Its Transcriptional Response to FXR in Zn-Induced Changes to Lipid Metabolism.International journal of molecular sciences · 2022Article
- Co-administration of obeticholic acid and simvastatin protects against high-fat diet-induced non-alcoholic steatohepatitis in mice.Experimental and therapeutic medicine · 2021Article
- Nuclear receptors FXR and SHP regulate protein N-glycan modifications in the liver.Science advances · 2021Article
- The Nuclear Farnesoid X Receptor Reduces p53 Ubiquitination and Inhibits Cervical Cancer Cell Proliferation.Frontiers in cell and developmental biology · 2021Article
- Review
- Genome-wide expression profiling reveals increased stability and mitochondrial energy metabolism of the human liver cell line HepaRG-CAR.Cytotechnology · 2020Article
- Farnesoid X receptor and bile acids regulate vitamin A storage.Scientific reports · 2019Article
- Hepatocyte nuclear receptor SHP suppresses inflammation and fibrosis in a mouse model of nonalcoholic steatohepatitis.The Journal of biological chemistry · 2018Article
- Activation of FXR promotes intestinal metaplasia of gastric cells via SHP-dependent upregulation of the expression of CDX2.Oncology letters · 2018Article
- Article
- Review
- Article
- Interleukin-6 Induces DEC1, Promotes DEC1 Interaction with RXRα and Suppresses the Expression of PXR, CAR and Their Target Genes.Frontiers in pharmacology · 2017Article
Corrections and comments
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundFarnesoid X receptor/retinoid X receptor-alpha (FXR/RXRα) is the master transcriptional regulator of bile salt synthesis and transport in liver and intestine. FXR is activated by bile acids, RXRα by the vitamin A-derivative 9-cis retinoic acid (9cRA). Remarkably, 9cRA inhibits binding of FXR/RXRα to its response element, an inverted repeat-1 (IR-1). Still, most FXR/RXRα target genes are maximally expressed in the presence of both ligands, including the small heterodimer partner (SHP). Here, we revisited the FXR/RXRα-mediated regulation of human SHP.
methodsA 579-bp hSHP promoter element was analyzed to locate FXR/chenodeoxycholic acid (CDCA)- and RXRα/9cRA-responsive elements. hSHP promoter constructs were analyzed in FXR/RXRα-transfected DLD-1, HEK293 and HepG2 cells exposed to CDCA, GW4064 (synthetic FXR ligand) and/or 9cRA. FXR-DNA interactions were analyzed by in vitro pull down assays.
resultshSHP promoter elements lacking the previously identified IR-1 (-291/-279) largely maintained their activation by FXR/CDCA, but were unresponsive to 9cRA. FXR-mediated activation of the hSHP promoter was primarily dependent on the -122/-69 region. Pull down assays revealed a direct binding of FXR to the -122/-69 sequence, which was abrogated by site-specific mutations in a binding site for the liver receptor homolog-1 (LRH-1) at -78/-70. These mutations strongly impaired the FXR/CDCA-mediated activation, even in the context of a hSHP promoter containing the IR-1. LRH-1 did not increase FXR/RXRα-mediated activation of hSHP promoter activity.
conclusionFXR/CDCA-activated expression of SHP is primarily mediated through direct binding to an LRH-1 binding site, which is not modulated by LRH-1 and unresponsive to 9cRA. 9cRA-induced expression of SHP requires the IR-1 that overlaps with a direct repeat-2 (DR-2) and DR-4. This establishes for the first time a co-stimulatory, but independent, action of FXR and RXRα agonists.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.