Roles for Bile Transporters in the Pathogenesis and Treatment of Liver and Intestinal Diseases Open Access

Truong, Jennifer (Fall 2022)

Permanent URL: https://etd.library.emory.edu/concern/etds/hq37vp81w?locale=en
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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