The goal of this application is to advance our understanding of the physiological roles of the intestinal bile acid transporters and their relationship to intestinal and metabolic disease. Bile acids play critical roles in the intestinal absorption of fats and fat-soluble vitamins, gut anti-microbial defenses, and as signaling molecules to modulate lipid and glucose metabolism. By regulating the flux of bile acids in the enterohepatic circulation, bile acid transporters control the compartmentalization of bile acids and modulate their physiological and pathophysiological actions. In the previous funding period, we demonstrated the importance of the Organic Solute Transporter Ost?-Ost? for maintenance of the enterohepatic circulation and bile acid homeostasis. The studies proposed in this renewal application will focus on expanding our understanding of the physiological roles of the intestinal bile acid transporters and their relationship to intestinal and metabolic disease. This includes identifying the mechanisms responsible for the intestinal adaptive response in the Ost? null mice, and the mechanisms by which blocking intestinal bile acid absorption protects against the development of high fat diet-induced obesity and metabolic syndrome. The studies in Specific Aim 1 are designed to further elucidate the in vivo functions of Ost?-Ost? by determining the mechanisms responsible for the intestinal adaptive response in Ost? null mice. Our studies demonstrated that regulation of bile acid and lipid metabolism is differentially affected by disruption of intestinal bile acid absorption at the apical versus basolateral membranes. Based on this work, the studies in Specific Aim 2 are designed to define the roles of ileal FGF15 expression and bile acid flux in the anti-obesity and hypoglycemic effects associated with interruption of the enterohepatic circulation of bile acids. The long-term goal of this work is to understand the role of bile acids in human gastrointestinal and metabolic disease, and translate those insights into new preventive measures and therapies.

Public Health Relevance

In addition to their well-established roles in lipid digestion and absorption, bile acids function as signaling molecules with potent metabolic actions. As such, it is not surprising that altered enterohepatic cycling of bile acids is associated with a wide variet of hepatic, gastrointestinal, and metabolic disorders. The studies in this proposal will provide new insights to the mechanisms controlling bile acid flux and facilitate the development of new approaches targeting bile acid pathways for therapeutic benefit.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK047987-21
Application #
8759081
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
1994-05-10
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
21
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Emory University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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; Karpen, Saul J (2015) Intestinal transport and metabolism of bile acids. J Lipid Res 56:1085-99
Kosters, Astrid; Dawson, Paul A (2015) The Na(+) -taurocholate cotransporting polypeptide knockout mouse: A new tool for study of bile acids and hepatitis B virus biology. Hepatology 62:19-21
Dawson, Paul A (2015) Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice. Dig Dis 33:382-7
Ferrebee, Courtney B; Dawson, Paul A (2015) Metabolic effects of intestinal absorption and enterohepatic cycling of bile acids. Acta Pharm Sin B 5:129-34
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
Karpen, Saul J; Dawson, Paul A (2015) Not all (bile acids) who wander are lost: the first report of a patient with an isolated NTCP defect. Hepatology 61:24-7
Vivian, Diana; Cheng, Kunrong; Khurana, Sandeep et al. (2014) Design and evaluation of a novel trifluorinated imaging agent for assessment of bile acid transport using fluorine magnetic resonance imaging. J Pharm Sci 103:3782-92
Vivian, Diana; Cheng, Kunrong; Khurana, Sandeep et al. (2014) In vivo performance of a novel fluorinated magnetic resonance imaging agent for functional analysis of bile acid transport. Mol Pharm 11:1575-82

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