title: beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes.
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.
authors.affiliation: Department of Pediatrics, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Jyoti
authors.initials: J
authors.lastname: Sinha
authors.forename: Frank
authors.initials: F
authors.lastname: Chen
authors.forename: Tamir
authors.initials: T
authors.lastname: Miloh
authors.forename: Robert C
authors.initials: RC
authors.lastname: Burns
authors.forename: Zhisheng
authors.initials: Z
authors.lastname: Yu
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Shneider
mesh_terms: D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D005704:Gallbladder / Q000166:cytology*; D005786:Gene Expression Regulation / Q000502:physiology; D006801:Humans; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
chemical_list: D004268:DNA-Binding Proteins; D005346:Fibroblast Growth Factors; D000090265:Klotho Proteins; D008565:Membrane Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C418622:Klb protein, mouse; C108526:fibroblast growth factor 15, mouse; C071908:sodium-bile acid cotransporter
references.citation: World J Gastroenterol. 2006 Jun 14;12(22):3553-63
references.pmid: 16773712
references.citation: J Biol Chem. 2007 Sep 14;282(37):26687-26695
references.pmid: 17623664
references.citation: Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3891-6
references.pmid: 18292224
references.citation: World J Gastroenterol. 2004 May 15;10(10):1440-6
references.pmid: 15133850
references.citation: J Biol Chem. 2001 Aug 3;276(31):28857-65
references.pmid: 11387316
references.citation: Hepatology. 2001 Nov;34(5):868-76
references.pmid: 11679956
references.citation: J Clin Invest. 2005 Aug;115(8):2202-8
references.pmid: 16075061
references.citation: J Biol Chem. 2007 Sep 14;282(37):27277-27284
references.pmid: 17627937
references.citation: Am J Physiol Gastrointest Liver Physiol. 2006 May;290(5):G912-22
references.pmid: 16357058
references.citation: Science. 1999 May 21;284(5418):1362-5
references.pmid: 10334992
references.citation: J Biol Chem. 2003 May 30;278(22):19909-16
references.pmid: 12456679
references.citation: Am J Physiol. 1996 Aug;271(2 Pt 1):G377-85
references.pmid: 8770054
references.citation: Trends Mol Med. 2003 Dec;9(12):558-64
references.pmid: 14659471
references.citation: Cell Metab. 2005 Oct;2(4):217-25
references.pmid: 16213224
references.citation: Genes Dev. 2003 Jul 1;17(13):1581-91
references.pmid: 12815072
references.citation: J Biol Chem. 2000 Apr 14;275(15):10918-24
references.pmid: 10753890
references.citation: J Biol Chem. 1991 Feb 25;266(6):3416-21
references.pmid: 1995604
references.citation: J Biol Chem. 2006 Mar 10;281(10):6120-3
references.pmid: 16436388
references.citation: Science. 1999 May 21;284(5418):1365-8
references.pmid: 10334993
references.citation: Mech Dev. 2000 Nov;98(1-2):115-9
references.pmid: 11044614
references.citation: Nat Med. 2006 Nov;12(11):1253-5
references.pmid: 17072310
references.citation: J Biol Chem. 1995 Nov 10;270(45):27228-34
references.pmid: 7592981
references.citation: Gastroenterology. 2002 Dec;123(6):2005-16
references.pmid: 12454857
references.citation: Nucleic Acids Res. 1989 Sep 12;17(17):7115
references.pmid: 2674908
references.citation: Hepatology. 2004 Jul;40(1):149-56
references.pmid: 15239098
references.citation: Mol Cell Biol. 2007 May;27(9):3417-28
references.pmid: 17339340
references.citation: Pediatr Res. 1997 Aug;42(2):189-94
references.pmid: 9262221
references.citation: J Clin Invest. 1997 Dec 1;100(11):2714-21
references.pmid: 9389734
references.citation: Nature. 1997 Nov 6;390(6655):45-51
references.pmid: 9363890
references.citation: J Biol Chem. 2004 Jan 23;279(4):2790-9
references.pmid: 14570929