ArticleGastroenterology2015
Nuclear Factor, Erythroid 2-Like 2 Regulates Expression of Type 3 Inositol 1,4,5-Trisphosphate Receptor and Calcium Signaling in Cholangiocytes.
Article in Gastroenterology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
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Who cites it
24 citing papers in PubMed, 50 citations in OpenAlex.
- Hsa_circ_0000711 can serve as a novel biomarker for primary biliary cholangitis by promoting disease progression through the regulation of miR-185-5p and NFATc3.RNA biology · 2026Article
- Astrocytic PERK Deficiency Drives Prefrontal Circuit Dysfunction and Depressive-Like Behaviors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Health position paper and redox perspectives - Bench to bedside transition for pharmacological regulation of NRF2 in noncommunicable diseases.Redox biology · 2025Review
- Steady-state regulation of COPII-dependent secretory cargo sorting by inositol trisphosphate receptors, calcium, and penta EF hand proteins.The Journal of biological chemistry · 2023Article
- Type 3 IP3 receptor: Its structure, functions, and related disease implications.Channels (Austin, Tex.) · 2023Review
- Interaction ofAntioxidants (Basel, Switzerland) · 2023Article
- Article
- iASPP suppresses Gp78-mediated TMCO1 degradation to maintain CaProceedings of the National Academy of Sciences of the United States of America · 2022Article
- CREB regulates the expression of type 1 inositol 1,4,5-trisphosphate receptors.Journal of cell science · 2021Article
- ITPR3 facilitates tumor growth, metastasis and stemness by inducing the NF-ĸB/CD44 pathway in urinary bladder carcinoma.Journal of experimental & clinical cancer research : CR · 2021Article
- Neutrophils interact with cholangiocytes to cause cholestatic changes in alcoholic hepatitis.Gut · 2021Article
- Inositol 1,4,5-trisphosphate receptor type 3 plays a protective role in hepatocytes during hepatic ischemia-reperfusion injury.Cell calcium · 2020Article
- Targeting the phosphoinositide-3-kinase/protein kinase B pathway in airway innate immunity.World journal of biological chemistry · 2020Review
- Genome-wide resolution peripheral blood methylome profiling reveals signatures for cholestatic liver disease.Epigenomics · 2020Article
- Type 3 Inositol 1,4,5-Trisphosphate Receptor Is Increased and Enhances Malignant Properties in Cholangiocarcinoma.Hepatology (Baltimore, Md.) · 2020Article
- Review
- Inositol 1,4,5-trisphosphate receptor in the liver: Expression and function.World journal of gastroenterology · 2019Review
- Expression of the type 3 InsPGut · 2019Article
- MicroRNA Sequencing Reveals the Effect of Different Levels of Non-Fibrous Carbohydrate/Neutral Detergent Fiber on Rumen Development in Calves.Animals : an open access journal from MDPI · 2019Article
- Polymorphism in the Promoter Region of NFE2L2 Gene Is a Genetic Marker of Susceptibility to Cirrhosis Associated with Alcohol Abuse.International journal of molecular sciences · 2019Article
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
BACKGROUND &
aimsMost cholestatic disorders are caused by defects in cholangiocytes. The type 3 isoform of the inositol 1,4,5-trisphosphate receptor (ITPR3) is the most abundant intracellular calcium release channel in cholangiocytes. ITPR3 is required for bicarbonate secretion by bile ducts, and its expression is reduced in intrahepatic bile ducts of patients with cholestatic disorders. We investigated whether the nuclear factor, erythroid 2-like 2 (NFE2L2 or NRF2), which is sensitive to oxidative stress, regulates expression of ITPR3.
methodsThe activity of the ITPR3 promoter was measured in normal human cholangiocyte (NHC) cells and primary mouse cholangiocytes. Levels of ITPR3 protein and messenger RNA were examined by immunoblot and polymerase chain reaction analyses, respectively. ITPR3 activity was determined by measuring calcium signaling in normal human cholangiocyte cells and secretion in isolated bile duct units. Levels of NRF2 were measured in liver tissues from rats with cholestasis (induced by administration of α-napthylisothiocyanate) and from patients with biliary diseases.
resultsWe identified a musculo-aponeurotic fibrosarcoma recognition element in the promoter of ITPR3 that bound NRF2 directly in NHC cells and mouse cholangiocytes. Increasing binding of NRF2 at this site resulted in chromatin remodeling that reduced promoter activity. Mutant forms of the musculo-aponeurotic fibrosarcoma recognition element did not bind NRF2. Activation of NRF2 with quercetin or by oxidative stress reduced expression of ITPR3 and calcium signaling in NHC cells; quercetin also reduced secretion by bile duct units isolated from rats. Knockdown of NRF2 with small interfering RNAs restored expression and function of ITPR3 in NHC cells incubated with quercetin. Bile ducts from rats with cholestasis and patients with cholangiopathic disorders expressed higher levels of NRF2 and lower levels of ITPR3 than ducts from control rats or patients with other liver disorders.
conclusionsThe transcription factor NRF2 binds to the promoter of ITPR3 to inhibit its expression in cholangiocytes, leading to reduced calcium signaling and bile duct secretion. This could be a mechanism by which oxidative stress inhibits these processes and contributes to cholangiopathies.
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