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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Sinha, Jyoti Chen, Frank Miloh, Tamir Burns, Robert C. Yu, Zhisheng Shneider, Benjamin L. |
| Description | Country affiliation: United States Author Affiliation: Sinha J ( Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA.) |
| Abstract | beta-Klotho, a newly described membrane protein, regulates bile acid synthesis. Fibroblast growth factor-15 (FGF-15) and FGF receptor-4 (FGFR4) knockout mice share a similar phenotype with beta-Klotho-deficient mice. FGF-15 secretion by the intestine regulates hepatic bile acid biosynthesis. The effects of beta-Klotho and FGF-15 on the ileal apical sodium bile transporter (ASBT) are unknown. beta-Klotho siRNA treatment of the mouse colon cancer cell line, CT-26, and the human intrahepatic biliary epithelial cells (HIBEC) resulted in upregulation of endogenous ASBT expression that was associated with reduced expression of the farnesoid X receptor (FXR) and the short heterodimer partner (SHP). Silencing beta-Klotho activated the ASBT promoter in CT-26, Mz-ChA-1 (human cholangiocarcinoma), and HIBEC cells. Site-directed mutagenesis of liver receptor homolog-1 (mouse) or retinoic acid receptor/retinoid X receptor (RAR/RXR) (human) cis-elements attenuated the basal activity of the ASBT promoter and abrogated its response to beta-Klotho silencing. siSHP, siFXR, or dominant-negative FXR treatment also eliminated the beta-Klotho response. FGF-15 secretion into cell culture media by CT-26 cells was diminished after siFGF-15 or sibeta-Klotho treatment and enhanced by chenodeoxycholic acid. Exogenous FGF-19 repressed ASBT protein expression in mouse ileum, gallbladder, and in HIBEC and repressed ASBT promoter activity in Caco-2, HIBEC, and Mz-ChA-1 cells. Promoter repression was dependent on the expression of FGFR4. These results indicate that both beta-Klotho and FGF-15/19 repress ASBT in enterocytes and cholangiocytes. These novel signaling pathways need to be considered in analyzing bile acid homeostasis. |
| File Format | HTM / HTML |
| ISSN | 01931857 |
| e-ISSN | 15221547 |
| DOI | 10.1152/ajpgi.90343.2008 |
| Journal | AJP: Gastrointestinal and Liver Physiology |
| Issue Number | 5 |
| Volume Number | 295 |
| Language | English |
| Publisher | American Physiological Society |
| Publisher Date | 2008-11-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Discipline Physiology Discipline Gastroenterology Enterocytes Metabolism Fibroblast Growth Factors Gallbladder Cytology Membrane Proteins Organic Anion Transporters, Sodium-dependent Symporters Animals Cell Line Dna-binding Proteins Genetics Gene Expression Regulation Physiology Mice Mice, Inbred C57bl Promoter Regions, Genetic Receptors, Cytoplasmic And Nuclear Signal Transduction Transcription Factors Research Support, N.i.h., Extramural |
| Content Type | Text |
| Resource Type | Article |
| Subject | Hepatology Physiology Physiology (medical) Gastroenterology |
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