The overall objective is to advance our understanding of the relationship of the Apical Sodium-dependent bile acid transporter (ASBT) and Organic Solute Transporter alpha-beta (OSTa?b?) to the pathogenesis of intestinalandhepatobiliarydisease.Collectively,ourfindingsstronglysupporttheconceptthatinadditionto its essential role in maintaining bile acid (BA) homeostasis, ASBT-OSTa?b? functions to protect the ileal epithelium against BA-induced injury. Moreover, the concept of a protective role for ASBT-OSTa?b? can potentially be extended to other BA-transporting epithelium and the cholehepatic shunt pathway by our identification of a dysfunctional mutation in OSTb? (SLC51B) in two pediatric patients with congenital diarrhea and features of liver disease. However, despite progress, the role of BAs and toxic bile in the pathogenesis of human disease and the opportunities for highly effective therapeutic intervention remain elusive. Guided by the applicants? recently published studies and strong preliminary data, three specific aimsareproposedtointerrogateASBT-OSTa?b??sroleinthepathogenesisofdiseaseandthemechanismof action of new BA-based therapies.
Specific Aim 1 is designed to elucidate the molecular mechanisms underlyingtheilealinjuryassociatedwithinactivationofOSTa?.Thiswillbeaccomplishedbyexaminingthe rolesforBAsandreactiveoxygenspecies(ROS)intheintestinalinjuryandrestitutionresponseinOsta?null mice,andtherolesoftheNox1andNrf2inthatprocess.
SpecificAim2 isdesignedtoelucidatetheroleof theASBTinthecholehepaticshuntingofBAsandtheactionsoftherapeuticandcytotoxicBAs.Thiswillbe accomplishedbyexaminingtherequirementforASBTincholehepaticshuntingofBAs,therequirementfor ASBT in the bicarbonate-rich hypercholeresis induced by therapeutic BAs such as UDCA and norUDCA, and the role of biliary ASBT in models of obstructive cholestasis.
Specific Aim 3 is designed to test the hypothesis that OSTa?b? functions to protect human hepatocytes and/or cholangiocytes from BA-induced injury. This will be accomplished using hepatocyte and cholangiocyte in vitro models. These innovative studies will yield novel insights to the the pathways underlying BA-induced injury and role of cholehepatic shunting of BAs in health and disease, with the goal of translating those insights into new preventive measuresandtreatments.
Theproposedresearchisrelevanttopublichealthbecauseitaddressesanurgentunmetneedtotreatforms of cholestatic liver disease. Medical interventions are under development that target specific bile acid (BA) receptorsorBAenterohepaticcyclingandappeartoprovideclinicalbenefitinPrimaryBiliaryCholangitisand inherited forms of liver disease such as Progressive Familial Intrahepatic Cholestasis. The studies in this proposalwillprovidekeyinsightstotheroleoftheBAtransportersandthecholehepaticshuntpathwayinthe pathogenesisofcholestaticliverdiseaseandthemechanismsofactionofnewBA-basedtherapies,thereby providingalogicalframeworktoacceleratetheirclinicaldevelopmentandimplementation.
|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|
|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|
|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|
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