The goal of this application is to advance our understanding of the transport pathways that maintain the enterohepatic circulation of bile acids, regulate bile acid flux, and protect against bile acid-induced injury. The foundation for this proposal is our recent identification of the heteromeric Organic Solute Transporter, Osta-Ostb, as a major mechanism for intestinal bile acid transport. In this application, we will focus on the mechanisms that support Osta-Ostb to maintain bile acid homeostasis and on the cytoprotective role of Osta-Ostb in the intestinal and colonic epithelium. Our previous studies demonstrated that intestinal bile acid absorption is impaired but not abolished in Osta-/- mice. Based on those findings, the studies in Specific Aim 1 are designed to test the hypothesis that the ABC transporters Mrp3 and Mrp4 are responsible for the residual bile acid transport and serve to protect the ileal epithelium from bile acid-induced damage in the Osta null mice. Our studies demonstrated that expression of Osta-Ostb is closely regulated by substrate to balance the bile acid flux and intracellular concentration. As such, dysregulation of Osta-Ostb expression may significantly alter bile acid and lipid metabolism, underscoring the importance of the recent finding that OSTa-OSTb expression is decreased in ileum from gallstone patients. Our work showed that the regulation of bile acid synthesis is profoundly altered in Osta-/- mice. Based on these observations, the studies in Specific Aim 2 are designed to elucidate the mechanisms responsible for the altered bile acid homeostasis in the Osta null mice. In the colon, the endogenous bacterial flora convert bile acids to more hydrophobic species capable of passively diffusing into epithelial cells. However, little is known about the mechanisms engaged to export bile acids and protect the colonocyte against bile acid-induced damage. Our preliminary data suggest that Osta-/- mice are more susceptible to dextran sodium sulfate-induced colonic injury as compared to littermate controls. These findings underscore the importance of the recent observation that OSTa expression is dramatically reduced in colon from patients with ulcerative colitis. Based on these findings, the studies in Specific Aim 3 are designed to test the hypothesis that Osta-Ostb is responsible for colonic basolateral bile acid transport and functions to protect the colon from the cytotoxic effects of bile acids. The long-term goal of this work is to understand the mechanisms that control the compartmentalization and enterohepatic circulation of bile acids and their relationship to human gastrointestinal and metabolic disease.

Public Health Relevance

Bile acids play critical roles in intestinal absorption of fats and fat-soluble vitamins, in gut anti- microbial defenses, and as signaling molecules to modulate lipid and glucose metabolism. However, bile acids are also cytotoxic and promote hepatic injury, intestinal inflammation, and gastrointestinal cancers. The studies in this proposal will provide new insights as to how the body controls the compartmentalization of bile acids and promote the development of new therapies for these hepatic and gastrointestinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK047987-19
Application #
8424987
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
1994-05-10
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2015-02-28
Support Year
19
Fiscal Year
2013
Total Cost
$310,489
Indirect Cost
$99,173
Name
Wake Forest University Health Sciences
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
937727907
City
Winston-Salem
State
NC
Country
United States
Zip Code
27157
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
Dawson, Paul A (2017) Roles of Ileal ASBT and OST?-OST? in Regulating Bile Acid Signaling. Dig Dis 35:261-266
Arab, Juan P; Karpen, Saul J; Dawson, Paul A et al. (2017) Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Hepatology 65:350-362
Sultan, Mutaz; Rao, Anuradha; Elpeleg, Orly et al. (2017) Organic Solute Transporter-beta (SLC51B) Deficiency in Two Brothers with Congenital Diarrhea and Features of Cholestasis. Hepatology :
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) Hepatic bile acid uptake in humans and mice: Multiple pathways and expanding potential role for gut-liver signaling. Hepatology 66:1384-1386
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
Raufman, Jean-Pierre; Dawson, Paul A; Rao, Anuradha et al. (2015) Slc10a2-null mice uncover colon cancer-promoting actions of endogenous fecal bile acids. Carcinogenesis 36:1193-200
Dial, Elizabeth J; Dawson, Paul A; Lichtenberger, Lenard M (2015) In vitro evidence that phosphatidylcholine protects against indomethacin/bile acid-induced injury to cells. Am J Physiol Gastrointest Liver Physiol 308:G217-22
Dawson, Paul A; Karpen, Saul J (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085-99

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