The objectives of this application are to advance understanding of mechanisms of disposition of the two major classes of cholesterol metabolites, namely bile acids and steroid conjugates, compounds that play important roles in a number of biological processes and human diseases. The background to this proposal is our demonstration that the organic solute transporter, Ost?-Ost?, plays a central role in mediating the disposition of these compounds. Ost?-Ost? is an unusual heteromeric transporter that is expressed in nearly all tissues, but is most abundant in the small intestine, kidney, liver, testis, adrenal gland, as well as other steroidogenic tissues. Our studies to date of the transporter's substrate specificity, transport mechanism, tissue distribution, subcellular localization, transcriptional regulation, as well as the phenotype of our recently characterized Ost?- deficient mice suggest that Ost?-Ost? is the major basolateral membrane exporter of bile acids and structurally related molecules. In particular, studies with Ost?-deficient mice revealed that these animals have a markedly diminished bile acid pool size, a defect in intestinal bile acid absorption, intestinal hypertrophy, growth retardation, and a decrease in serum cholesterol and triglyceride levels. Because the enterohepatic circulation of bile acids is essential for processes such as intestinal absorption of dietary fats and vitamins, cholesterol homeostasis, bile flow, and biliary lipid secretion, these data suggest that Ost?-Ost? also indirectly regulates lipid homeostasis. The goals of this proposal are to test two hypotheses: first, that Ost? is both a chaperone and a structural component of the functional Ost?-Ost? transporter;and second, that the Ost?-Ost?-mediated transport of bile acids and related steroids modulates lipid homeostasis.
The specific aims are: (1) Identify specific amino acid residues of Ost? that are critical for heterodimerization, trafficking, and/or functional activity;and (2) Examine whether Ost?-/- mice are resistant to age related, dietary, or genetically induced obesity. Overall, these studies will provide important information on the mechanism by which Ost?-Ost? mediates bile acid and steroid disposition, on the potential contribution of the transporter to lipid homeostasis, and will provide structure-function information that should facilitate the development of therapeutics targeting this transporter.

Public Health Relevance

Our recent studies have provided strong evidence that the organic solute transporter, Ost?-Ost?, plays a central role in mediating the disposition of bile acids and steroid conjugates, compounds that play important roles in a number of biological processes and human diseases, including cholestatic and fatty liver diseases, malabsorption syndrome, and cholelithiasis. The goals of this proposal are to test the hypotheses that Ost? is both a chaperone and a structural component of the functional Ost?-Ost? transporter, and that the Ost?-Ost?- mediated transport of bile acids and related molecules modulates lipid homeostasis. Overall, the proposed studies will provide important information on the mechanism by which Ost?-Ost? mediates bile acid and steroid disposition, on the potential contribution of the transporter to lipid homeostasis, and will provide structure- function information that should facilitate the development of therapeutics targeting this transporter. Such therapeutics could be of benefit in many human conditions related to imbalances in bile acid or lipid homeostasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK067214-08
Application #
8307406
Study Section
Xenobiotic and Nutrient Disposition and Action Study Section (XNDA)
Program Officer
Grey, Michael J
Project Start
2004-04-01
Project End
2014-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
8
Fiscal Year
2012
Total Cost
$332,677
Indirect Cost
$117,352
Name
University of Rochester
Department
Public Health & Prev Medicine
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Wheeler, Sadie G; Hammond, Christine L; Jornayvaz, François R et al. (2014) Ost?-/- mice exhibit altered expression of intestinal lipid absorption genes, resistance to age-related weight gain, and modestly improved insulin sensitivity. Am J Physiol Gastrointest Liver Physiol 306:G425-38
Ballatori, Nazzareno; Christian, Whitney V; Wheeler, Sadie G et al. (2013) The heteromeric organic solute transporter, OSTýý-OSTýý/SLC51: a transporter for steroid-derived molecules. Mol Aspects Med 34:683-92
Madejczyk, Michael S; Ballatori, Nazzareno (2012) The iron transporter ferroportin can also function as a manganese exporter. Biochim Biophys Acta 1818:651-7
Christian, Whitney V; Li, Na; Hinkle, Patricia M et al. (2012) ?-Subunit of the Ost?-Ost? organic solute transporter is required not only for heterodimerization and trafficking but also for function. J Biol Chem 287:21233-43
Ballatori, Nazzareno (2011) Pleiotropic functions of the organic solute transporter Ost?-Ost?. Dig Dis 29:13-7
Soroka, Carol J; Velazquez, Heino; Mennone, Albert et al. (2011) Ost? depletion protects liver from oral bile acid load. Am J Physiol Gastrointest Liver Physiol 301:G574-9
Soroka, Carol J; Mennone, Albert; Hagey, Lee R et al. (2010) Mouse organic solute transporter alpha deficiency enhances renal excretion of bile acids and attenuates cholestasis. Hepatology 51:181-90
Krance, Suzanne M; Keng, Peter C; Palis, James et al. (2010) Transient glutathione depletion determines terminal differentiation in HL-60 cells. Oxid Med Cell Longev 3:53-60
Fang, Fang; Christian, Whitney V; Gorman, Sadie G et al. (2010) Neurosteroid transport by the organic solute transporter OSTýý-OSTýý. J Neurochem 115:220-33
Shi, Shujie; Notenboom, Sylvia; Dumont, Mark E et al. (2010) Identification of human gene products containing Pro-Pro-x-Tyr (PY) motifs that enhance glutathione and endocytotic marker uptake in yeast. Cell Physiol Biochem 25:293-306

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