The apical sodium-dependent bile acid transporter (ASBT) is the major carrier protein involved in intestinal reclamation of bile salts. Complete genetic disruption of its activity leads to pathologic bile acid induced diarrhea in humans, while partial inhibition can be used to treat hypercholesterolemia and cholestasis. ASBT is expressed on the apical surface of ileal enterocytes, renal tubules, and cholangiocytes. In the rat ileum, ASBT undergoes a biphasic pattern of developmental expression. Bile acid responsiveness of ASBT is species specific. ASBT is down regulated in the ileitis and up regulated by corticosteroids. Adaptation by ASBT after intestinal resection is dependent upon the length of residual ileum. These changes in ASBT expression are controlled at the level of transcription and mRNA stability. The rat, mouse, and human ASBT promoters have been cloned in my laboratory. HNF-1alpha, AP-1 and LRH-1 are critical elements in the transcriptional regulation of ASBT. This proposal will define the molecular mechanisms involved in the regulation of the ASBT gene. Transcriptional regulation will be studied with chimeric luciferase promoter reporter constructs, DNA:protein gel shift analysis, and transgenic mice. Molecular mechanisms of transcriptional modulation of ASBT gene expression will be analyzed in normal physiology and pathologic states (altered bile acid homeostasis, ileal inflammation and intestinal resection). The role of mRNA stability will be assessed by identification of mRNA destabilizing elements in the ASBT transcript and by characterization of RNA:protein interactions. Cell-free systems and/or transgenic animals will be utilized to assess the role of these elements in developmental-stage and organ specific expression. The results of these studies will be highly significant in light of the crucial role that ASBT plays in human health and disease. The ASBT gene also represents a valuable model of important and poorly defined biological processes in the intestine, such as transcriptional regulation of ontogeny and tissue specificity and the role of mRNA stability in intestinal gene regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054165-05A2
Application #
6610722
Study Section
Special Emphasis Panel (ZRG1-ALTX-4 (02))
Program Officer
May, Michael K
Project Start
1997-09-30
Project End
2008-03-31
Budget Start
2003-04-21
Budget End
2004-03-31
Support Year
5
Fiscal Year
2003
Total Cost
$339,000
Indirect Cost
Name
Mount Sinai School of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Soler, Dellys M; Ghosh, Ayantika; Chen, Frank et al. (2014) A single element in the 3'UTR of the apical sodium-dependent bile acid transporter controls both stabilization and destabilization of mRNA. Biochem J 462:547-53
Ghosh, Ayantika; Chen, Frank; Banerjee, Swati et al. (2014) c-Fos mediates repression of the apical sodium-dependent bile acid transporter by fibroblast growth factor-19 in mice. Am J Physiol Gastrointest Liver Physiol 306:G163-71
Chen, Frank; Shyu, Ann-Bin; Shneider, Benjamin L (2011) Hu antigen R and tristetraprolin: counter-regulators of rat apical sodium-dependent bile acid transporter by way of effects on messenger RNA stability. Hepatology 54:1371-8
Chen, Frank; Ellis, Ewa; Strom, Stephen C et al. (2010) ATPase Class I Type 8B Member 1 and protein kinase C zeta induce the expression of the canalicular bile salt export pump in human hepatocytes. Pediatr Res 67:183-7
Annaba, Fadi; Ma, Ke; Kumar, Pradeep et al. (2010) Ileal apical Na+-dependent bile acid transporter ASBT is upregulated in rats with diabetes mellitus induced by low doses of streptozotocin. Am J Physiol Gastrointest Liver Physiol 299:G898-906
Sinha, Jyoti; Chen, Frank; Miloh, Tamir et al. (2008) beta-Klotho and FGF-15/19 inhibit the apical sodium-dependent bile acid transporter in enterocytes and cholangiocytes. Am J Physiol Gastrointest Liver Physiol 295:G996-G1003
Frankenberg, Tamara; Miloh, Tamir; Chen, Frank Y et al. (2008) The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology 48:1896-905
Neimark, Ezequiel; Chen, Frank; Li, Xiaoping et al. (2006) c-Fos is a critical mediator of inflammatory-mediated repression of the apical sodium-dependent bile acid transporter. Gastroenterology 131:554-67
Frankenberg, Tamara; Rao, Anuradha; Chen, Frank et al. (2006) Regulation of the mouse organic solute transporter alpha-beta, Ostalpha-Ostbeta, by bile acids. Am J Physiol Gastrointest Liver Physiol 290:G912-22
Pan, Debra H; Chen, Frank; Neimark, Ezequiel et al. (2005) FTF and LRH-1, two related but different transcription factors in human Caco-2 cells: their different roles in the regulation of bile acid transport. Biochim Biophys Acta 1732:31-7

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