Many of the major carriers responsible for the enterohepatic circulation have been identified in recent years. Notably absent from that list is the basolateral membrane transporter responsible for the efflux of bile acids from the ileal enterocyte, renal proximal tubule cell, and cholangiocyte. This has hindered understanding the molecular mechanism and regulation of bile acid flux through the enterohepatic circulation. We have recently applied a gene profiling approach to the ileal bile acid transporter knockout mouse in order to identify a candidate basolateral bile acid transporter, Osta/b. The goal of the proposed work is to test the hypothesis that Osta/b is the major ileal basolateral bile acid transporter and to understand its regulation. To accomplish these goals, three specific aims are proposed.
Aim 1 : To test the hypothesis that the heteromeric Osta/b transporter is an ileal basolateral bile acid transporter. For this aim, the following questions will be investigated. 1) What tissues express Osta/b mRNA and protein? 2) What is the cellular localization of the Osta/b protein? 3) Does Osta/b promote bile acid efflux in transfected MDCK cells, a model polarized epithelial cell? 4) Does Osta/b expression correlate with the appearance of transcellular bile acid flux in intestinal development and in Caco-2 cells programmed to differentiate? 5) Is Osta/b expression necessary for basolateral membrane transport in Caco-2 cells, a model intestinal polarized epithelial cell? Aim 2: To use knockout mouse models to determine the relative contribution of Osta/b to intestinal bile acid transport. For this study, bile acid metabolism including fecal bile acid excretion, bile acid pool size, and intestinal bile acid absorption will be examined in Mrp3 and Osta null mice.
Aim 3 : To elucidate the mechanism responsible for bile acid regulation of the ileal Osta/b. The goal of this aim is to elucidate the transcriptional mechanisms responsible for the regulation of the Osta and Ostb genes by bile acids. For this aim, the regulation of mouse Osta/b by bile acid feeding or depletion will be investigated in vivo. The transcriptional regulation of the Osta gene will be investigated in vitro using transfected promoter constructs and transcription factor binding assays. The long-range goal of this work is to understand the mechanism and regulation of ileal bile acid transport as it relates to dietary lipid metabolism in normal and disease states.
|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|
|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|
|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|
|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|
|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|
Showing the most recent 10 out of 38 publications