Roles for Bile Transporters in the Pathogenesis and Treatment of Liver and Intestinal Diseases Öffentlichkeit
Truong, Jennifer (Fall 2022)
Published
Abstract
The detergent properties of bile acids (BAs) are essential to facilitate dietary fat digestion and absorption. However, BAs also play important roles in cholesterol homeostasis, hepatic bile formation, biliary lipid excretion, and as signaling molecules to regulate lipid and glucose metabolism. Disruption of BA enterohepatic cycling and signaling plays a role in the pathogenesis or progression of liver, gastrointestinal and metabolic diseases. Conversely, BA-based treatments targeting BA transport and signaling represent new therapeutic opportunities. In the studies that follow we used cell-based and knockout mouse models to investigate the relationship of BA hydrophobicity and BA-associated injury, and to elucidate the therapeutic mechanism of actions of the cholehepatic drug norUrsodeoxycholic acid (norUDCA) and BA enterohepatic circulation blockers. The BA pool is more hydrophilic and cytoprotective in mice versus humans, partially limiting their use as models to study hydrophobic BA-associated injury. We generated mice lacking Cyp2c70, the murine liver enzyme responsible for the synthesis of 6-hydroxylated hydrophilic BAs. We show that Cyp2c70 KO mice have a more human-like hydrophobic BA pool composition and develop cholestatic liver disease. The liver disease can be effectively treated using an ileal apical sodium-dependent BA transporter inhibitor, which reduced the total hepatic BA burden. The bile acid analog, norUrsodeoxycholic acid (norUDCA) is in late-stage clinical development to treat liver disease, however the molecular mechanisms responsible for its potent therapeutic ability to induce protective bicarbonate-rich bile flow (hypercholeresis) had not been identified. We show that norUDCA does not require the major BA transporters, and likely undergoes cholehepatic shunting and directly stimulates the Ca2+-activated Cl- channel TMEM16A to induce biliary bicarbonate secretion. The hepatocellular response to cytotoxic bile acids is a primary contributor to the pathogenesis of cholestatic liver injury. However less is known about the response of other tissues to cytotoxic BAs. We explored the consequences of BA accumulation in an Osta KO mouse model of intestinal BA stasis and used therapeutic BAs and BA enterohepatic circulation blockers to investigate the mechanisms of ileal injury. These studies collectively provide additional mechanistic understanding of BA’s role in the pathogenesis and treatment of disease.
Table of Contents
Chapter 1: Introduction to Bile Acid Metabolism and Scope of Dissertation
Introduction
Bile Acid Structure and Physical Properties
Biosynthesis of Bile Acids
Biosynthetic Pathway
Inherited Defects in Bile Acid Synthesis
Regulation of Bile Acid Biosynthesis
Secondary Metabolism of Bile Acids
Enterohepatic Circulation of Bile Acids
Hepatic Bile Acid Transport
Intestinal Transport of Bile Acids
Bile acids as Signaling Molecules
Scope of the Dissertation
References
Chapter 2: Ileal bile acid transporter inhibition in Cyp2c70 KO mice ameliorates cholestatic liver injury
Abstract
Introduction
Materials and Methods
Results
IBAT inhibition protects against Cyp2c70 deficiency-associated liver disease
IBAT Inhibition reduces expression of inflammatory pathway genes
IBAT inhibition alters BA metabolism and reduces hepatic BA content in Cyp2c70 KO mice
Detergency of the hepatic BA pool in Cyp2c70 KO mice
Discussion
Acknowledgements
Supplementary Material
References
Chapter 3: Active Enterohepatic Cycling is Not Required for the Choleretic Actions of 24-norUrsodeoxycholic Acid in Mice
Abstract
Introduction
Materials and Methods
Results
Discussion
Acknowledgements
Supplementary Material
References
Chapter 4: Ileal Injury and Restitution of Organic Solute Transporter alpha-deficient Mice
Abstract
Introduction
Materials and Methods
Results
Ileal bile acid transporter inhibition reverses ileal injury in Ostα-/- mice
Bile acid sequestrant Colesevelam does not improve ileal phenotype in Ostα-/- mice
Therapeutic bile acid ursodeoxycholic acid does reduce antioxidant response in Ostα-/- mice
Ileal injury in Ostα-/- mice is not dependent on NADPH oxidase 1 (Nox1)
Broad quenching of reactive oxygen species with n-acetylcysteine (NAC) does not rescue ileal injury in Ostα-/- mice
Discussion
Supplementary Material
References
Chapter 5: Discussion and Future Directions
Impact and Significance
Future Directions
Final Thoughts
About this Dissertation
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