Liver fibrogenesis is a complex wound-healing process elicited by various chronic toxic stimuli. Hepatocyte apoptosis is a main feature of chronic inflammation in the liver, and recently we have demonstrated a direct link between hepatocyte apoptosis and fibrogenic activity in the liver. At the center of liver fibrogenesis are the hepatic stellate cells, which by phagocytosing apoptotic bodies of hepatocytes induce fibrogenic signaling pathways and production of extracellular matrix. Activation of the NADPH oxidase (NOX) is a crucial step in the induction of the fibrogenic activity following phagocytosis. Thus, our HYPOTHESIS is that NOX2 activation with superoxide production in HSC is a key event during liver fibrogenesis. To address this hypothesis our SPECIFIC AIMS will be to study the following areas where NOX2 activation may play a key role: 1. NOX2 increases HSC phagocytic activity of HSC 2. Phagocytosis and NOX2 activation induce fibrogenic signaling pathways 3. Phagocytosis and NOX2 activation induce liver fibrogenesis in vivo. The data emanating from this proposal will help define the mechanistic links between hepatocyte apoptosis resulting from chronic liver injury, phagocytosis and NOX2 activation in HSC, and the resulting oxidative damage and fibrogenic response. Furthermore, the proposed studies will yield important data on the early activation of HSC during fibrogenesis which may translate into designing rational therapeutic approaches to prevent progression of fibrosis.

Public Health Relevance

Liver cirrhosis is a leading cause of morbidity and mortality worldwide. Hepatic stellate cell activation with the resulting production of extracellular matrix is a central event in the fibrogenic process;however, the mechanism by which this occurs is not fully understood. We have previously shown that stellate cells phagocytose apoptotic bodies from hepatocytes and this directly induces their fibrogenic activation via activation of the NADPH oxidase (NOX). Here we propose that NOX2 is a key enzyme in liver fibrogenesis and its activation in stellate cells leads to upregulation of profibrogenic genes. Information originating from the successful completion of the proposed experiments has the potential to be developed into strategies to prevent and treat liver fibrosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK083283-05
Application #
8616053
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2010-03-20
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$310,199
Indirect Cost
$104,774
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Tian, Jijing; Yang, Guoxiang; Chen, Huan-Yuan et al. (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202-4213
Torok, Natalie J (2015) Vascular adhesion protein 1 in nonalcoholic steatohepatitis: a novel biomarker? Hepatology 62:1313-5
Torok, Natalie J (2015) Update on Alcoholic Hepatitis. Biomolecules 5:2978-86
Serizawa, Nobuko; Tian, Jijing; Fukada, Hiroo et al. (2015) Galectin 3 regulates HCC cell invasion by RhoA and MLCK activation. Lab Invest 95:1145-56
Bettaieb, Ahmed; Jiang, Joy X; Sasaki, Yu et al. (2015) Hepatocyte Nicotinamide Adenine Dinucleotide Phosphate Reduced Oxidase 4 Regulates Stress Signaling, Fibrosis, and Insulin Sensitivity During Development of Steatohepatitis in Mice. Gastroenterology 149:468-80.e10
Jiang, Joy X; Török, Natalie J (2013) Liver Injury and the Activation of the Hepatic Myofibroblasts. Curr Pathobiol Rep 1:215-223
Jiang, Joy X; Chen, Xiangling; Fukada, Hiroo et al. (2013) Advanced glycation endproducts induce fibrogenic activity in nonalcoholic steatohepatitis by modulating TNF-*-converting enzyme activity in mice. Hepatology 58:1339-48
Jiang, Joy X; Chen, Xiangling; Hsu, Daniel K et al. (2012) Galectin-3 modulates phagocytosis-induced stellate cell activation and liver fibrosis in vivo. Am J Physiol Gastrointest Liver Physiol 302:G439-46
Jiang, Joy X; Chen, Xiangling; Serizawa, Nobuko et al. (2012) Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med 53:289-96
Devaraj, Sridevi; Torok, Natalie (2011) Leptin: the missing link between obesity and heart disease? Atherosclerosis 217:322-3

Showing the most recent 10 out of 13 publications