In lipid metabolism, bile acids play a critical role in the digestion of dietary fat and the absorption of dietary metabolites and cholesterol. To maintain their enterohepatic circulation, bile acids are conserved by active ileal uptake. Using isolated intestinal sections and enterocytes, the kinetic properties and chemical specificity of ileal bile acid transport has been examined. However, the proteins responsible for transport have not been isolated, and the process has not been studied at the molecular level. This has hindered understanding the mechanism of ileal bile acid transport, its regulation, and its role in bile acid and cholesterol metabolism. The proposed research will employ a recently identified bile acid transporter cDNA clone to examine the regulation and mechanism of the ileal bile acid transport. The following questions will be addressed: 1. What are the general properties of the ileal bile acid transporter? Bile acid transport across the ileum is believed to be mediated by a Na+- dependent transporter on the brush border membrane. To identify and characterize the transporter, my laboratory used an expression cloning strategy to isolate a candidate cDNA clone (IBAT) for the ileal bile acid transporter. To verify the identity of the candidate cDNA and extend previous studies of the transporter, IBAT's transport and expression properties will be determined. 2. Is the ileal bile acid transporter regulated by bile acid availability? Very recent in vivo studies have suggested that ileal bile acid transport activity is regulated by bile acid availability and may be a crucial determinant of bile acid and cholesterol homeostasis. To determine a) whether the transporter is regulated by changes in hamster intestinal bile acid availability (as previously hypothesized) and b) what level this reulation occurs, ileal Na+-dependent bile acid transporter activity, protein, mRNA, and gene transcription levels will be examined. 3. How does the ileal bile acid transporter function to carry bile acids across the enterocyte? To begin studying the cellular mechanism of bile acid transport, CaCo-2 cells will be used as a model system to express the ileal bile acid transporter cDNA. IBAT's transport properties will studied to test the hypothesis that the brush border membrane transporter is the rate limiting step in transcellular trafficking of bile acids across the ileal epithelium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29DK047987-04
Application #
2414867
Study Section
General Medicine A Subcommittee 2 (GMA)
Project Start
1994-05-10
Project End
1999-04-30
Budget Start
1997-05-01
Budget End
1998-04-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041418799
City
Winston-Salem
State
NC
Country
United States
Zip Code
27106
Ferrebee, Courtney B; Li, Jianing; Haywood, Jamie et al. (2018) Organic Solute Transporter ?-? Protects Ileal Enterocytes From Bile Acid-Induced Injury. Cell Mol Gastroenterol Hepatol 5:499-522
Sultan, Mutaz; Rao, Anuradha; Elpeleg, Orly et al. (2018) Organic solute transporter-? (SLC51B) deficiency in two brothers with congenital diarrhea and features of cholestasis. Hepatology 68:590-598
Li, Jianing; Dawson, Paul A (2018) Animal models to study bile acid metabolism. Biochim Biophys Acta Mol Basis Dis :
Dawson, Paul A; Parini, Paolo (2018) Hepatic thyroid hormone receptor ?1 agonism: good for lipids, good for bile? J Lipid Res 59:1551-1553
Dawson, Paul A (2017) Hepatic bile acid uptake in humans and mice: Multiple pathways and expanding potential role for gut-liver signaling. Hepatology 66:1384-1386
Thompson, Cayla A; Wojta, Kevin; Pulakanti, Kirthi et al. (2017) GATA4 Is Sufficient to Establish Jejunal Versus Ileal Identity in the Small Intestine. Cell Mol Gastroenterol Hepatol 3:422-446
Dawson, Paul A (2017) Roles of Ileal ASBT and OST?-OST? in Regulating Bile Acid Signaling. Dig Dis 35:261-266
Dawson, Paul A; Setchell, Kenneth D R (2017) Will the real bile acid sulfotransferase please stand up? Identification of Sult2a8 as a major hepatic bile acid sulfonating enzyme in mice. J Lipid Res 58:1033-1035
Rao, Anuradha; Kosters, Astrid; Mells, Jamie E et al. (2016) Inhibition of ileal bile acid uptake protects against nonalcoholic fatty liver disease in high-fat diet-fed mice. Sci Transl Med 8:357ra122
Dawson, Paul A (2016) Toxic bile and sclerosing cholangitis: Is there a role for pharmacological interruption of the bile acid enterohepatic circulation? Hepatology 63:363-4

Showing the most recent 10 out of 26 publications