Mechanisms of Hepatoprotection in a Murine Model of Bile Acid-Induced Intrahepatic Cholestasis

Persistent Link:
http://hdl.handle.net/10150/194264
Title:
Mechanisms of Hepatoprotection in a Murine Model of Bile Acid-Induced Intrahepatic Cholestasis
Author:
Beilke, Lisa D
Issue Date:
2008
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
There are many causes of cholestasis, which results when the flow of bile acids is slowed or stopped. Bile acids are hydrophobic molecules synthesized from cholesterol in the liver, and when present in excess, are cytotoxic to cell membranes. Treatment options for cholestasis are limited, and if left untreated or inadequately treated, many patients will require a liver transplant; thus, underscoring the importance of successfully managing this disease. Activation of nuclear receptors in animal models has been shown to be hepatoprotective during bile acid-induced cholestasis; however, the mechanisms underlying the hepatoprotective effects are poorly understood. Therefore, the over-arching goal of this project is to glean an improved comprehension of the mechanisms of hepatoprotection during bile acid-induced cholestasis. All of the studies involve administration of CAR activators phenobarbital (PB), oltipraz (OPZ), 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene [TCPOBOP (TC)] or corn oil (CO) to C57BL/6 wild type (WT), or WT and CAR knockout (CAR-/-) mice prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Efflux transport proteins such as Mrps 3 and 4 are known to be up-regulated during cholestasis, and this was the first topic of exploration. Unexpectedly, the expression of efflux transporters was not consistently up-regulated in protected mice. However, a decrease in total liver bile acid concentrations was observed. These changes in hepatic bile acids indicated that bile acid biosynthesis may be relevant to hepatoprotection. Indeed decreases in total and individual bile acids correlated with hepatoprotection, and Cyp8b1 expression was also increased which could be suggestive of a shift in the bile acid biosynthesis pathway towards the formation of less toxic bile acid species. CAR may also have a role in cell death via apoptosis by altering Bcl-2 protein expression. Although apoptosis was decreased in hepatoprotected mice, an increase in the expression of Mcl-1 and Bcl-xL was not observed, suggesting hepatoprotection is not a direct result of CAR-induced Mcl-1 expression. These findings add significantly to the body of knowledge surrounding cholestatic liver disease and suggest that studies aimed toward manipulation of nuclear receptors are worthy of further exploration.
Type:
text; Electronic Dissertation
Keywords:
Cholestasis; bile acid; biosynthesis; apoptosis; constitutive androstane receptor
Degree Name:
PhD
Degree Level:
doctoral
Degree Program:
Pharmacology & Toxicology; Graduate College
Degree Grantor:
University of Arizona
Advisor:
Cherrington, Nathan J
Committee Chair:
Cherrington, Nathan J

Full metadata record

DC FieldValue Language
dc.language.isoENen_US
dc.titleMechanisms of Hepatoprotection in a Murine Model of Bile Acid-Induced Intrahepatic Cholestasisen_US
dc.creatorBeilke, Lisa Den_US
dc.contributor.authorBeilke, Lisa Den_US
dc.date.issued2008en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractThere are many causes of cholestasis, which results when the flow of bile acids is slowed or stopped. Bile acids are hydrophobic molecules synthesized from cholesterol in the liver, and when present in excess, are cytotoxic to cell membranes. Treatment options for cholestasis are limited, and if left untreated or inadequately treated, many patients will require a liver transplant; thus, underscoring the importance of successfully managing this disease. Activation of nuclear receptors in animal models has been shown to be hepatoprotective during bile acid-induced cholestasis; however, the mechanisms underlying the hepatoprotective effects are poorly understood. Therefore, the over-arching goal of this project is to glean an improved comprehension of the mechanisms of hepatoprotection during bile acid-induced cholestasis. All of the studies involve administration of CAR activators phenobarbital (PB), oltipraz (OPZ), 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene [TCPOBOP (TC)] or corn oil (CO) to C57BL/6 wild type (WT), or WT and CAR knockout (CAR-/-) mice prior to induction of intrahepatic cholestasis using the secondary bile acid lithocholic acid (LCA). Efflux transport proteins such as Mrps 3 and 4 are known to be up-regulated during cholestasis, and this was the first topic of exploration. Unexpectedly, the expression of efflux transporters was not consistently up-regulated in protected mice. However, a decrease in total liver bile acid concentrations was observed. These changes in hepatic bile acids indicated that bile acid biosynthesis may be relevant to hepatoprotection. Indeed decreases in total and individual bile acids correlated with hepatoprotection, and Cyp8b1 expression was also increased which could be suggestive of a shift in the bile acid biosynthesis pathway towards the formation of less toxic bile acid species. CAR may also have a role in cell death via apoptosis by altering Bcl-2 protein expression. Although apoptosis was decreased in hepatoprotected mice, an increase in the expression of Mcl-1 and Bcl-xL was not observed, suggesting hepatoprotection is not a direct result of CAR-induced Mcl-1 expression. These findings add significantly to the body of knowledge surrounding cholestatic liver disease and suggest that studies aimed toward manipulation of nuclear receptors are worthy of further exploration.en_US
dc.typetexten_US
dc.typeElectronic Dissertationen_US
dc.subjectCholestasisen_US
dc.subjectbile aciden_US
dc.subjectbiosynthesisen_US
dc.subjectapoptosisen_US
dc.subjectconstitutive androstane receptoren_US
thesis.degree.namePhDen_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplinePharmacology & Toxicologyen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorCherrington, Nathan Jen_US
dc.contributor.chairCherrington, Nathan Jen_US
dc.contributor.committeememberGandolfi, A. Jayen_US
dc.contributor.committeememberFutscher, Bernard W.en_US
dc.contributor.committeememberRegan, John W.en_US
dc.identifier.proquest2886en_US
dc.identifier.oclc659749539en_US
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