HEPATIC FIBROSIS: MOLECULAR MECHANISMS

Summary

Principal Investigator: Mario Chojkier
Abstract: We and others have reported the isolation of a clone encoding for the CCAAT/Enhancer Binding Protein (C/EBP)(, and we have established that C/EBP( is a critical modulator of both gene expression and the G1/S phase transition of the cell cycle. Activation of ribosomal S6-kinase (RSK)- 2 and phosphorylation of C/EBP( on its activation domain plays a major role in cell survival, at least in part, by binding to the procaspase 8 complex and preventing its self-cleavage and activation. Our recent discovery identifies a novel non-transcriptional role of C/EBP( acting as an inhibitor of the caspase 8 pathway. It remains to be determined what are the mechanisms involved, and whether this inhibition is direct and/or indirect. We have determined that the MAPK-RSK-C/EBP( signaling cascade modulates expression of FLIPL, a critical inhibitor of procaspase 8. Also, we have found that C/EBP( associates with FLIPL and that this association is down-regulated by FAS signaling. As expected, the non-phosphorylatable C/EBP(Ala217 mutant prevents stellate cell activation induced by the collagen type I matrix or growth factor/MAPK/RSK signaling cascade, while the phosphorylation mimic C/EBP(Glu217 mutant blocks stellate cell apoptosis initiated by death receptors or proteasome inhibitors (caspase 8 pathway). This proposal will study the mechanism(s) by which C/EBP( modulates the extrinsic apoptotic pathway in hepatic stellate cells. The specific aims of this proposal are to assess: 1. The regulation of FLIPL activity by MAPK-RSK-C/EBP( signaling in stellate cells. 2. The role of C/EBP( phosphorylation on stellate cell survival. 3. The modulation of stellate cell survival in C/EBP(Glu217 transgenic mice.
Funding Period: 1987-07-01 - 2010-05-31
more information: NIH RePORT

Top Publications

  1. ncbi Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients
    Martina Buck
    Veterans Affairs San Diego Healthcare System, San Diego, CA Department of Medicine, University of California, San Diego, La Jolla, CA Biomedical Sciences Program, University of California, San Diego, La Jolla, CA
    Hepatology 59:1052-9. 2014
  2. pmc Pioglitazone decreases hepatitis C viral load in overweight, treatment naïve, genotype 4 infected-patients: a pilot study
    Mario Chojkier
    Department of Medicine, San Diego VA Healthcare System, San Diego, California, United States of America
    PLoS ONE 7:e31516. 2012
  3. pmc C/EBPβ-Thr217 phosphorylation signaling contributes to the development of lung injury and fibrosis in mice
    Martina Buck
    Department of Medicine, VA Healthcare Center, San Diego, California, United States of America
    PLoS ONE 6:e25497. 2011
  4. pmc Decreased Jun-D and myogenin expression in muscle wasting of human cachexia
    Sonia Ramamoorthy
    Department of Surgery, University of California San Diego, San Diego, California, USA
    Am J Physiol Endocrinol Metab 297:E392-401. 2009
  5. ncbi Severe hepatocellular injury with apoptosis induced by a hepatitis C polymerase inhibitor
    Ariel Feldstein
    Department of Pediatrics, Cleveland Clinic, Cleveland, OH, USA
    J Clin Gastroenterol 43:374-81. 2009
  6. ncbi Targeting ribosomal S-6 kinase for the prevention and treatment of liver injury and liver fibrosis
    Martina Buck
    Moores Cancer Center, University of California, San Diego, California, USA
    Drug News Perspect 21:301-6. 2008
  7. pmc Direct infection and replication of naturally occurring hepatitis C virus genotypes 1, 2, 3 and 4 in normal human hepatocyte cultures
    Martina Buck
    Department of Medicine and Moores Cancer Center, University of California, La Jolla, California, United States of America
    PLoS ONE 3:e2660. 2008
  8. ncbi A novel domain of BRCA1 interacts with p53 in breast cancer cells
    Martina Buck
    Department of Medicine, Veterans Healthcare Medical Center, San Diego, CA 92161, USA
    Cancer Lett 268:137-45. 2008
  9. ncbi C/EBPbeta associates with caspase 8 complex proteins and modulates apoptosis in hepatic stellate cells
    Martina Buck
    Department of Medicine and Cancer Center, Veterans Healthcare Medical Center and University of California, San Diego, CA 92161, USA
    J Clin Gastroenterol 41:S295-9. 2007
  10. ncbi C/EBPbeta phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin
    Martina Buck
    Department of Medicine, University of California San Diego, and Veterans Affairs Healthcare System, San Diego, CA 92161, USA
    Am J Physiol Cell Physiol 293:C1788-96. 2007

Scientific Experts

Detail Information

Publications13

  1. ncbi Novel inflammatory biomarkers of portal pressure in compensated cirrhosis patients
    Martina Buck
    Veterans Affairs San Diego Healthcare System, San Diego, CA Department of Medicine, University of California, San Diego, La Jolla, CA Biomedical Sciences Program, University of California, San Diego, La Jolla, CA
    Hepatology 59:1052-9. 2014
    ..Our diagnostic test was not efficient in predicting HVPG ≥ 12 mmHg...
  2. pmc Pioglitazone decreases hepatitis C viral load in overweight, treatment naïve, genotype 4 infected-patients: a pilot study
    Mario Chojkier
    Department of Medicine, San Diego VA Healthcare System, San Diego, California, United States of America
    PLoS ONE 7:e31516. 2012
    ..A secondary aim was to assess whether Prednisone, a drug that induces insulin resistance and stimulates HCV viral entry and replication in replicon culture systems, increases HCV viral load in this population...
  3. pmc C/EBPβ-Thr217 phosphorylation signaling contributes to the development of lung injury and fibrosis in mice
    Martina Buck
    Department of Medicine, VA Healthcare Center, San Diego, California, United States of America
    PLoS ONE 6:e25497. 2011
    ....
  4. pmc Decreased Jun-D and myogenin expression in muscle wasting of human cachexia
    Sonia Ramamoorthy
    Department of Surgery, University of California San Diego, San Diego, California, USA
    Am J Physiol Endocrinol Metab 297:E392-401. 2009
    ..These studies show that these molecular pathways are modulated in association with muscle wasting in patients with cancer or AIDS, and whether or not they cause muscle wasting remains to be determined...
  5. ncbi Severe hepatocellular injury with apoptosis induced by a hepatitis C polymerase inhibitor
    Ariel Feldstein
    Department of Pediatrics, Cleveland Clinic, Cleveland, OH, USA
    J Clin Gastroenterol 43:374-81. 2009
    ..To describe the mechanisms of severe hepatocellular injury with apoptosis in 2 patients receiving hepatitis C virus (HCV)-796...
  6. ncbi Targeting ribosomal S-6 kinase for the prevention and treatment of liver injury and liver fibrosis
    Martina Buck
    Moores Cancer Center, University of California, San Diego, California, USA
    Drug News Perspect 21:301-6. 2008
    ..Thus, appropriate RSK inhibitors may be beneficial in the prevention and treatment of liver injury and liver fibrosis. These issues will be discussed in this review...
  7. pmc Direct infection and replication of naturally occurring hepatitis C virus genotypes 1, 2, 3 and 4 in normal human hepatocyte cultures
    Martina Buck
    Department of Medicine and Moores Cancer Center, University of California, La Jolla, California, United States of America
    PLoS ONE 3:e2660. 2008
    ..The current Huh-7 systems use cloned, synthetic HCV RNA expressed in hepatocellular carcinoma cells to produce virions, but these cells cannot be infected with naturally occurring HCV obtained from infected patients...
  8. ncbi A novel domain of BRCA1 interacts with p53 in breast cancer cells
    Martina Buck
    Department of Medicine, Veterans Healthcare Medical Center, San Diego, CA 92161, USA
    Cancer Lett 268:137-45. 2008
    ..These results suggest that a novel domain of BRCA1 may interact with p53 in breast cancer cells...
  9. ncbi C/EBPbeta associates with caspase 8 complex proteins and modulates apoptosis in hepatic stellate cells
    Martina Buck
    Department of Medicine and Cancer Center, Veterans Healthcare Medical Center and University of California, San Diego, CA 92161, USA
    J Clin Gastroenterol 41:S295-9. 2007
    ..To analyze the role of C/EBPbeta phosphorylation on hepatic stellate cell survival/cell death...
  10. ncbi C/EBPbeta phosphorylation rescues macrophage dysfunction and apoptosis induced by anthrax lethal toxin
    Martina Buck
    Department of Medicine, University of California San Diego, and Veterans Affairs Healthcare System, San Diego, CA 92161, USA
    Am J Physiol Cell Physiol 293:C1788-96. 2007
    ..These findings suggest that C/EBPbeta may play a critical role in anthrax pathogenesis, at least in macrophages...
  11. ncbi The effect of hepatic insufficiency on the safety and pharmacokinetics of paricalcitol (Zemplar)
    Robert A Carr
    Department of Clinical Pharmacokinetics, Abbott Laboratories, Abbott Park, Illinois 60064 6104, USA
    Nephron Clin Pract 103:c100-5. 2006
    ..Paricalcitol is highly protein bound, extensively metabolized and eliminated primarily by hepatobiliary excretion. This study was designed to determine if hepatic disease alters the pharmacokinetics or affects the safety of paricalcitol...
  12. ncbi Inhibition of albumin synthesis in chronic diseases: molecular mechanisms
    Mario Chojkier
    Department of Medicine and Cancer Center, University of California San Diego, San Diego, CA 92161, USA
    J Clin Gastroenterol 39:S143-6. 2005
    ....
  13. ncbi Troglitazone and liver injury: in search of answers
    Mario Chojkier
    Department of Medicine and Cancer Center, Veterans Affairs Healthcare System and University of California, San Diego, CA 92161, USA
    Hepatology 41:237-46. 2005