Molecular Pathogenesis of Cystic Fibrosis Liver Disease

Summary

Principal Investigator: Martin Carey
Abstract: [unreadable] DESCRIPTION (provided by applicant): The frequency of liver disease in humans with cystic fibrosis (CF) (focal biliary fibrosis leading to multilobular cirrhosis) ranges up to 43%, with prevalence increasing with age. Multilobular cirrhosis manifesting clinically with portal hypertension has become the third leading cause of morbidity and premature death in CF, and when pulmonary disease is controlled with or without lung transplantation, liver disease is the leading cause of death. The etiology, mechanisms and pathogenesis of CF liver disease are unknown, and currently ursodeoxycholic acid is prescribed without compelling evidence of its efficacy. Extending preliminary studies from this laboratory, the ?F508 and G551D murine models of CF and wild-type (WT) mice will be studied: 1) to explore the hepatobiliary secretory abnormalities of pH, bilirubins, electrolytes and biliary lipids utilizing biophysical, pathophysiological and physical-chemical approaches; 2) to determine the pathogenesis of enteric hyperbilirubinbilia and to correlate this with ileal pH abnormalities, bile salt malabsorption, hepatic bile pH and liver disease; 3) to elucidate the pathophysiology of bile salt malabsorption as a cause of induced enterohepatic cycling of unconjugated bilirubin (UCB), focusing on the ileal bile salt transporter and its response to less alkaline lumenal pH; in addition, to study intestinally hCFTR-rescued CF mice to verify the molecular nature of the intestinal defect; 4) to image and quantify age and gender-related liver histology and ultrastructural studies to detect deposits of metal bilirubinates intraductally and in biliary epithelial cells using transmission and scanning electron microscopy coupled with atomic emission spectroscopy, and to quantify the pathobiology of UCB-induced periductal inflammation, fibrogenesis and obliterative cholangitis; 5) to prevent and treat chronic liver disease of CF mice by a) targeting the biliary tree with norUDCA to increase pH of hepatic bile, b) targeting UCB formation and absorption in the distal gut by non-absorbed polymers with covalently linked D-glucaro-1,4-lactone or cholic acid, and c) targeting bile salt malabsorption using colesevelam HCI to prevent solubility of UCB or by normalizing the lumenal pH using amiloride, a carbonic anhydrase agonist, or by upregulating ASBT activity with budesonide. The molecular insights from these hypothesis-driven specific aims should provide data, molecular understanding and agents that are translatable to humans with CF and lead to new modalities for prevention and treatment of CF liver disease. [unreadable] [unreadable]
Funding Period: 2005-09-15 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. pmc Pathophysiological preconditions promoting mixed "black" pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis
    Folke Freudenberg
    Department of Medicine, Harvard Medical School and Harvard Digestive Diseases Center Department of Medicine, Gastroenterology Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA
    Am J Physiol Gastrointest Liver Physiol 299:G205-14. 2010
  2. ncbi QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains
    Henning Wittenburg
    The Jackson Laboratory, Bar Harbor, ME, USA
    J Lipid Res 47:1780-90. 2006
  3. pmc Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8(-/-) mice
    Helen H Wang
    Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard Digestive Diseases Center, Boston, MA, USA
    Hepatology 45:998-1006. 2007
  4. pmc T-cell function is critical for murine cholesterol gallstone formation
    Kirk J Maurer
    Department of Biological Engineering, Massachusetts Institute of Technology, Boston, Massachusetts, USA
    Gastroenterology 133:1304-15. 2007
  5. pmc Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
    Cell Metab 7:125-34. 2008
  6. pmc Pathophysiological basis of liver disease in cystic fibrosis employing a DeltaF508 mouse model
    Folke Freudenberg
    Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Am J Physiol Gastrointest Liver Physiol 294:G1411-20. 2008
  7. pmc Hepatic insulin resistance directly promotes formation of cholesterol gallstones
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA
    Nat Med 14:778-82. 2008
  8. pmc Biliary lipids and cholesterol gallstone disease
    David Q H Wang
    Department of Medicine, Harvard Medical School, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, and Harvard Digestive Diseases Center, and Brigham and Women s Hospital, Boston, MA 02115, USA
    J Lipid Res 50:S406-11. 2009
  9. pmc Roles of infection, inflammation, and the immune system in cholesterol gallstone formation
    Kirk J Maurer
    Division of Gastroenterology, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
    Gastroenterology 136:425-40. 2009

Scientific Experts

Detail Information

Publications9

  1. pmc Pathophysiological preconditions promoting mixed "black" pigment plus cholesterol gallstones in a DeltaF508 mouse model of cystic fibrosis
    Folke Freudenberg
    Department of Medicine, Harvard Medical School and Harvard Digestive Diseases Center Department of Medicine, Gastroenterology Division, Brigham and Women s Hospital, 75 Francis St, Boston, MA 02115, USA
    Am J Physiol Gastrointest Liver Physiol 299:G205-14. 2010
    ..This is an initial step toward unraveling the molecular basis of CF gallstone disease and constitutes a framework for investigating animal models of CF with more severe biliary disease, as well as the human disease...
  2. ncbi QTL mapping for genetic determinants of lipoprotein cholesterol levels in combined crosses of inbred mouse strains
    Henning Wittenburg
    The Jackson Laboratory, Bar Harbor, ME, USA
    J Lipid Res 47:1780-90. 2006
    ....
  3. pmc Quantifying anomalous intestinal sterol uptake, lymphatic transport, and biliary secretion in Abcg8(-/-) mice
    Helen H Wang
    Department of Medicine, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard Digestive Diseases Center, Boston, MA, USA
    Hepatology 45:998-1006. 2007
    ....
  4. pmc T-cell function is critical for murine cholesterol gallstone formation
    Kirk J Maurer
    Department of Biological Engineering, Massachusetts Institute of Technology, Boston, Massachusetts, USA
    Gastroenterology 133:1304-15. 2007
    ..Although gallbladder inflammation is believed to be common during cholelithogenesis, the role of immunologic factors is unknown...
  5. pmc Hepatic insulin resistance is sufficient to produce dyslipidemia and susceptibility to atherosclerosis
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215, USA
    Cell Metab 7:125-34. 2008
    ..Thus, insulin resistance at the level of the liver is sufficient to produce the dyslipidemia and increased risk of atherosclerosis associated with the metabolic syndrome...
  6. pmc Pathophysiological basis of liver disease in cystic fibrosis employing a DeltaF508 mouse model
    Folke Freudenberg
    Department of Medicine, Harvard Medical School, Boston, MA 02115, USA
    Am J Physiol Gastrointest Liver Physiol 294:G1411-20. 2008
    ..This study of the earliest stages of CF liver disease provides a framework for investigating the molecular pathophysiology of more advanced disease in murine models and in humans with CF...
  7. pmc Hepatic insulin resistance directly promotes formation of cholesterol gallstones
    Sudha B Biddinger
    Research Division, Joslin Diabetes Center, 1 Joslin Place, Boston, Massachusetts 02215, USA
    Nat Med 14:778-82. 2008
    ..As a result, after twelve weeks on a lithogenic diet, all of the LIRKO mice develop gallstones. Thus, hepatic insulin resistance provides a crucial link between the metabolic syndrome and increased cholesterol gallstone susceptibility...
  8. pmc Biliary lipids and cholesterol gallstone disease
    David Q H Wang
    Department of Medicine, Harvard Medical School, Liver Center and Gastroenterology Division, Beth Israel Deaconess Medical Center, and Harvard Digestive Diseases Center, and Brigham and Women s Hospital, Boston, MA 02115, USA
    J Lipid Res 50:S406-11. 2009
    ....
  9. pmc Roles of infection, inflammation, and the immune system in cholesterol gallstone formation
    Kirk J Maurer
    Division of Gastroenterology, Brigham and Women s Hospital, Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA
    Gastroenterology 136:425-40. 2009
    ....