Bile secretion is a major function of the liver which is frequently impaired in diseases of the liver resulting in the syndrome of cholestasis. The long term objectives of this grant, funded continuously by NIDDK since 1973, have been to characterize the basic transport mechanisms in hepatocytes at the cellular and molecular level that determine the secretion of bile and to define alterations in these mechanisms that result in cholestatic liver disease . In this request for extension of this MERIT award, the specific aims continue much as before. They are Aim 1-A: Mechanisms of Transcriptional Regulation of MRP4/Mrp4 and its role in the adaptive response to cholestasis Aim 1-B: To evaluate the role of basolateral Osta deletion/inhibition in kidney and intestine as a protective effect in cholestasis and hyperlipidemia.
Aim 1 -C: To evaluate the role of MDR3/Mdr2 as therapeutic targets forfenofibrate (FF) and all-trans retinoic acid in human and rat hepatocytes and, if so, by what mechanism.
These aims are a continuation of our work to understand the molecular mechanisms for adaptive regulation of hepatocyte membrane that are important determinants of the adaptive response in cholestatic liver injury - and to devise new therapies based on this information. In particular in Aim 1-A and B we will continue to characterize the transcriptional regulators of the human MRP4 promoter as well as to continue to assess the role that the heteromeric, facilitated bile salt transporter, OSTo-OSTp plays in the adaptive response to cholestasis.
Aim #1 -C determines the molecular mechanisms by which fenofibrate improves cholestatic liver disease and the role of all-trans retinoic acid in this process.
AIM # 2: (previously Aim #3) continues to characterize post-transcriptional mechanisms of regulation of the expression of canalicular ABC transporters by investigating the functional roles of interacting proteins involved in maintaining canalicular apical membrane structural polarity of Mrp2.
AIM #3 : Comparative studies of bile acid transport in marine vertebrates. We will continue to utilize marine animals as comparative models for bile acid transporters in the enterohepatic circulation.

Public Health Relevance

Understanding how the liver adapts to injury resulting from impairment of bile production (known as cholestasis). Bile formation is a vital function &impairment in a variety of cholestasis liver diseases often resulting in progressive cholestasis and liver failure that can result in death or liver transplantation. Understanding the mechanism at the cellular/molecular level, we can design new therapeutic strategies that will augment adaptive responses &retard or reverse the progression of potentially fatal liver disorders.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Method to Extend Research in Time (MERIT) Award (R37)
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No Study Section (in-house review) (NSS)
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Sherker, Averell H
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Yale University
New Haven
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Kulkarni, Supriya R; Soroka, Carol J; Hagey, Lee R et al. (2016) Sirtuin 1 activation alleviates cholestatic liver injury in a cholic acid-fed mouse model of cholestasis. Hepatology 64:2151-2164
Chai, Jin; Cai, Shi-Ying; Liu, Xiaocong et al. (2015) Canalicular membrane MRP2/ABCC2 internalization is determined by Ezrin Thr567 phosphorylation in human obstructive cholestasis. J Hepatol 63:1440-8
Ghonem, Nisanne S; Assis, David N; Boyer, James L (2015) Fibrates and cholestasis. Hepatology 62:635-43
Boyer, James L (2015) The origins of hepatobiliary and gastrointestinal physiology. Hepatology 61:1452-4
Li, Man; Mennone, Albert; Soroka, Carol J et al. (2015) Na(+) /H(+) exchanger regulatory factor 1 knockout mice have an attenuated hepatic inflammatory response and are protected from cholestatic liver injury. Hepatology 62:1227-36
Cai, Shi-Ying; Mennone, Albert; Soroka, Carol J et al. (2014) All-trans-retinoic acid improves cholestasis in α-naphthylisothiocyanate-treated rats and Mdr2-/- mice. J Pharmacol Exp Ther 349:94-8
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Ghonem, Nisanne S; Ananthanarayanan, Meenakshisundaram; Soroka, Carol J et al. (2014) Peroxisome proliferator-activated receptor * activates human multidrug resistance transporter 3/ATP-binding cassette protein subfamily B4 transcription and increases rat biliary phosphatidylcholine secretion. Hepatology 59:1030-42
Wheeler, Sadie G; Hammond, Christine L; Jornayvaz, François R et al. (2014) Ostα-/- 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

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