ArticleHepatology (Baltimore, Md.)2018
Farnesoid X receptor signaling activates the hepatic X-box binding protein 1 pathway in vitro and in mice.
Article in Hepatology (Baltimore, Md.), 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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Who cites it
19 citing papers in PubMed, 48 citations in OpenAlex.
- Article
- Integrating deep learning and molecular dynamics simulations for FXR antagonist discovery.Molecular diversity · 2025Article
- Bile acids regulation of cellular stress responses in liver physiology and diseases.eGastroenterology · 2024Article
- Article
- Expression of unfolded protein response genes in post-transplantation liver biopsies.BMC gastroenterology · 2022Article
- Inositol-requiring enzyme 1α/X-box protein 1 pathway expression is impaired in pediatric cholestatic liver disease explants.PloS one · 2022Article
- Hepatic X-Box Binding Protein 1 and Unfolded Protein Response Is Impaired in Weanling Mice With Resultant Hepatic Injury.Hepatology (Baltimore, Md.) · 2021Article
- Small heterodimer partner (SHP) aggravates ER stress in Parkinson's disease-linked LRRK2 mutant astrocyte by regulating XBP1 SUMOylation.Journal of biomedical science · 2021Article
- The long and the small collide: LncRNAs and small heterodimer partner (SHP) in liver disease.Molecular and cellular endocrinology · 2021Review
- Endogenous glutamate determines ferroptosis sensitivity via ADCY10-dependent YAP suppression in lung adenocarcinoma.Theranostics · 2021Article
- Norcholic Acid Promotes Tumor Progression and Immune Escape by Regulating Farnesoid X Receptor in Hepatocellular Carcinoma.Frontiers in oncology · 2021Article
- Pediatric Cholestatic Liver Disease: Review of Bile Acid Metabolism and Discussion of Current and Emerging Therapies.Frontiers in medicine · 2020Review
- Potential of guggulsterone, a farnesoid X receptor antagonist, in the prevention and treatment of cancer.Exploration of targeted anti-tumor therapy · 2020Review
- Article
- Article
- Betulinic acid alleviates endoplasmic reticulum stress-mediated nonalcoholic fatty liver disease through activation of farnesoid X receptors in mice.British journal of pharmacology · 2019Article
- Endoplasmic reticulum stress and liver diseases.Liver research (Beijing, China) · 2019Article
- Calnexin Depletion by Endoplasmic Reticulum Stress During Cholestasis Inhibits the NaHepatology communications · 2018Article
- Update on FXR Biology: Promising Therapeutic Target?International journal of molecular sciences · 2018Review
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Authors and funding
11 authors at 3 institutions in 3 countries.
Funding
Abstract
Bile acids are endogenous ligands of the nuclear receptor, farnesoid X receptor (FXR), and pharmacological FXR modulators are under development for the treatment of several liver disorders. The inositol-requiring enzyme 1α/X-box binding protein 1 (IRE1α/XBP1) pathway of the unfolded protein response (UPR) is a protective cellular signaling pathway activated in response to endoplasmic reticulum (ER) stress. We investigated the role of FXR signaling in activation of the hepatic XBP1 pathway. Mice were treated with deoxycholic acid (DCA), cholestyramine, GW4064, or underwent bile duct ligation (BDL), and hepatic UPR activation was measured. Huh7-Ntcp and HepG2 cells were treated with FXR agonists, inhibitor, small interfering RNA (siRNA), or small heterodimer partner (SHP) siRNA to determine the mechanisms of IRE1α/XBP1 pathway activation. DCA feeding and BDL increased and cholestyramine decreased expression of hepatic XBP1 spliced (XBP1s). XBP1 pathway activation increased in Huh7-Ntcp and HepG2 cells treated with bile acids, 6α-ethyl-chenodeoxycholic acid (6-ECDCA) or GW4064. This effect decreased with FXR knockdown and treatment with the FXR inhibitor guggulsterone. FXR agonists increased XBP1 splicing and phosphorylated IRE1α (p-IRE1α) expression. Overexpression of SHP similarly increased XBP1 splicing, XBP1s, and p-IRE1α protein expression. SHP knockdown attenuated FXR agonist-induced XBP1s and p-IRE1α protein expression. Co-immunoprecipitation (Co-IP) assays demonstrate a physical interaction between overexpressed green fluorescent protein (GFP)-SHP and FLAG-IRE1α in HEK293T cells. Mice treated with GW4064 had increased, and FXR and SHP null mice had decreased, basal Xbp1s gene expression.
conclusionFXR signaling activates the IRE1α/XBP1 pathway in vivo and in vitro. FXR pathway activation increases XBP1 splicing and enhances p-IRE1α expression. These effects are mediated, at least in part, by SHP. IRE1α/XBP1 pathway activation by bile acids and pharmacological FXR agonists may be protective during liver injury and may have therapeutic implications for liver diseases. (Hepatology 2018;68:304-316).
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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.