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)
Type
Research Project (R01)
Project #
2R01DK047987-21
Application #
8759081
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Sherker, Averell H
Project Start
Project End
Budget Start
Budget End
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
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
Dawson, Paul A; Karpen, Saul J (2014) Bile acids reach out to the spinal cord: new insights to the pathogenesis of itch and analgesia in cholestatic liver disease. Hepatology 59:1638-41
Won, Christina S; Lan, Tian; Vandermolen, Karen M et al. (2013) A modified grapefruit juice eliminates two compound classes as major mediators of the grapefruit juice-fexofenadine interaction: an in vitro-in vivo "connect". J Clin Pharmacol 53:982-90
Dawson, Paul A (2013) Novel regulator of enterohepatic bile acid signaling protects against hypercholesterolemia. Cell Metab 17:816-8
Lan, Tian; Haywood, Jamie; Dawson, Paul A (2013) Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoEýýý/ýýý mice. Atherosclerosis 229:374-80
Lan, Tian; Rao, Anuradha; Haywood, Jamie et al. (2012) Mouse organic solute transporter alpha deficiency alters FGF15 expression and bile acid metabolism. J Hepatol 57:359-65
Debray, Dominique; Rainteau, Dominique; Barbu, Veronique et al. (2012) Defects in gallbladder emptying and bile Acid homeostasis in mice with cystic fibrosis transmembrane conductance regulator deficiencies. Gastroenterology 142:1581-91.e6
Dawson, Paul A (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol :169-203
Tang, Weiqing; Jia, Lin; Ma, Yinyan et al. (2011) Ezetimibe restores biliary cholesterol excretion in mice expressing Niemann-Pick C1-Like 1 only in liver. Biochim Biophys Acta 1811:549-55
Dawson, Paul A (2010) Liver disease without flipping: new functions of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1. Hepatology 51:1885-7

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