دورية أكاديمية
Hepatocyte nuclear factor 4α regulates the expression of intestinal epithelial Na + /H + exchanger isoform 3.
| العنوان: | Hepatocyte nuclear factor 4α regulates the expression of intestinal epithelial Na + /H + exchanger isoform 3. |
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| المؤلفون: | Muthusamy S; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois., Jeong JJ; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois., Cheng M; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois., Bonzo JA; Center for Cancer Research, National Cancer Institute , Bethesda, Maryland., Kumar A; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois., Gonzalez FJ; Center for Cancer Research, National Cancer Institute , Bethesda, Maryland., Borthakur A; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois., Dudeja PK; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois.; Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois., Saksena S; Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois at Chicago , Chicago, Illinois.; Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois., Malakooti J; Jesse Brown Veterans Affairs Medical Center , Chicago, Illinois. |
| المصدر: | American journal of physiology. Gastrointestinal and liver physiology [Am J Physiol Gastrointest Liver Physiol] 2018 Jan 01; Vol. 314 (1), pp. G14-G21. Date of Electronic Publication: 2017 Sep 07. |
| نوع المنشور: | Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S. |
| اللغة: | English |
| بيانات الدورية: | Publisher: American Physiological Society Country of Publication: United States NLM ID: 100901227 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1522-1547 (Electronic) Linking ISSN: 01931857 NLM ISO Abbreviation: Am J Physiol Gastrointest Liver Physiol Subsets: MEDLINE |
| أسماء مطبوعة: | Original Publication: Bethesda, MD : American Physiological Society |
| مواضيع طبية MeSH: | Hepatocyte Nuclear Factor 4/*metabolism , Intestinal Mucosa/*metabolism , Sodium-Hydrogen Exchanger 3/*metabolism, Binding Sites ; Caco-2 Cells ; Gene Expression Regulation ; HCT116 Cells ; Hepatocyte Nuclear Factor 4/genetics ; Humans ; Promoter Regions, Genetic ; Protein Binding ; Sodium-Hydrogen Exchanger 3/genetics |
| مستخلص: | Na + /H + exchanger isoform 3 (NHE3) plays a key role in coupled electroneutral NaCl absorption in the mammalian intestine. Reduced NHE3 expression or function has been implicated in the pathogenesis of diarrhea associated with inflammatory bowel disease (IBD) or enteric infections. Our previous studies revealed transcriptional regulation of NHE3 by various agents such as TNF-α, IFN-γ, and butyrate involving transcription factors Sp1 and Sp3. In silico analysis revealed that the NHE3 core promoter also contains a hepatocyte nuclear factor 4α (HNF-4α) binding site that is evolutionarily conserved in several species suggesting that HNF-4α has a role in NHE3 regulation. Nhe3 mRNA levels were reduced in intestine-specific Hnf4α-null mice. However, detailed mechanisms of NHE3 regulation by HNF-4α are not known. We investigated the regulation of NHE3 gene expression by HNF-4α in vitro in the human intestinal epithelial cell line C2BBe1 and in vivo in intestine-specific Hnf4α-null ( Hnf4α ΔIEpC ) and control ( Hnf4α fl/fl ) mice. HNF-4α knockdown by short interfering RNA in C2BBe1 cells significantly decreased NHE3 mRNA and NHE3 protein levels. Gel mobility shift and chromatin immunoprecipitation assays revealed that HNF-4α directly interacts with the HNF-4α motif in the NHE3 core promoter. Site-specific mutagenesis on the HNF-4α motif decreased, whereas ectopic overexpression of HNF-4α increased, NHE3 promoter activity. Furthermore, loss of HNF-4α in Hnf4α ΔIEpC mice decreased colonic Nhe3 mRNA and NHE3 protein levels. Our results demonstrate a novel role for HNF-4α in basal regulation of NHE3 expression. These studies represent an important and novel target for therapeutic intervention in IBD-associated diarrhea. NEW & NOTEWORTHY Our studies for the first time show that hepatocyte nuclear factor 4α directly regulates NHE3 promoter activity and its basal expression in the intestine. |
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| معلومات مُعتمدة: | I01 BX002867 United States BX BLRD VA; I01 BX002687 United States BX BLRD VA; R01 DK054016 United States DK NIDDK NIH HHS; R01 DK092441 United States DK NIDDK NIH HHS; I01 BX002011 United States BX BLRD VA; R01 DK081858 United States DK NIDDK NIH HHS |
| فهرسة مساهمة: | Keywords: C2BBe1 cells; Hnf4aΔIEpC mice; NaCl absorption; transcriptional regulation |
| المشرفين على المادة: | 0 (HNF4A protein, human) 0 (Hepatocyte Nuclear Factor 4) 0 (SLC9A3 protein, human) 0 (Sodium-Hydrogen Exchanger 3) |
| تواريخ الأحداث: | Date Created: 20170909 Date Completed: 20190226 Latest Revision: 20230815 |
| رمز التحديث: | 20230815 |
| مُعرف محوري في PubMed: | PMC5866373 |
| DOI: | 10.1152/ajpgi.00225.2017 |
| PMID: | 28882825 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1522-1547 |
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| DOI: | 10.1152/ajpgi.00225.2017 |