Hepatoprotective Mechanisms of Systemic Bile Acid Transporter Inhibitors

The overarching goal of this application is to advance our understanding of the role of the Apical sodium- dependent bile acid (BA) transporter (ASBT; also called IBAT) in the pathogenesis of cholestatic liver disease and associated kidney injury, and to elucidate the therapeutic mechanisms of action of systemically acting

ASBT inhibitors. In addition to ileal enterocytes, ASBT is expressed by kidney proximal tubule epithelial cells to limit BA loss in urine. ASBT is also expressed by cholangiocytes in the liver, where ASBT can mediate cholehepatic shunting of BAs. In contrast to ileum, much less is known regarding the ASBT’s role in those

tissue compartments in cholestatic liver disease or whether ASBT inhibition in kidney and biliary tract may have therapeutic benefit or deleterious effects. BAs have been implicated in a disorder called Cholemic Nephropathy (also called Bile Cast Nephropathy) and may be an underestimated contributor to kidney injury

in patients with liver disease. Guided by the applicant’s previously published work and strong preliminary data, two specific aims are proposed to address those gaps. Specific Aim 1 is designed to elucidate the kidney ASBT’s contribution to the hepatoprotective actions of systemic ASBT inhibition and define the role of kidney

ASBT in the pathogenesis of cholestatic liver disease-associated kidney injury. This will be accomplished using a novel kidney-specific ASBT knockout, state-of-the-art imaging approaches, and surgical and genetic models of cholestasis, including models with a “humanized” BA pool (Cyp2c70 knockout mice). The time

course and extent of liver and kidney injury will be determined to elucidate the relationship of kidney ASBT and urinary BA elimination to development of the hepatic and associated kidney injury. Human renal tubule organoids will be used to interrogate molecular mechanisms by which BAs alone or in combination with other

liver-derived cholephiles induce renal proximal tubule cell toxicity. Specific Aim 2 is designed to define the role of the biliary tract ASBT in the pathogenesis of cholestatic liver disease and the hepatoprotective actions of systemic ASBT inhibition. This will be accomplished using a novel liver-specific ASBT knockout mouse,

state-of-the-art imaging approaches, and surgical and genetic models of cholestasis, including models with a “humanized” BA pool (Cyp2c70 knockout mice). The time course and extent of liver injury will be determined to elucidate the relationship of cholangiocyte ASBT and cholehepatic BA shunting to development of

hepatobiliary disease. These innovative studies will yield novel and potentially paradigm-changing insights to the contribution of kidney and biliary tract BA reabsorption to the pathogenesis of cholestatic liver disease and the associated kidney injury (Cholemic Nephropathy). The findings are predicted to be impactful and will

guide development of new, safe, and effective approaches to treat the multi-organ damaged associated with cholestasis.