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 #
5R01DK083283-03
Application #
8225287
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2010-03-20
Project End
2015-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
3
Fiscal Year
2012
Total Cost
$310,759
Indirect Cost
$105,334
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
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; Torok, Natalie J (2013) Liver Injury and the Activation of the Hepatic Myofibroblasts. Curr Pathobiol Rep 1:215-223
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; Venugopal, Senthil; Serizawa, Nobuko et al. (2010) Reduced nicotinamide adenine dinucleotide phosphate oxidase 2 plays a key role in stellate cell activation and liver fibrogenesis in vivo. Gastroenterology 139:1375-84
Jiang, Joy X; Mikami, Kenichiro; Venugopal, Senthil et al. (2009) Apoptotic body engulfment by hepatic stellate cells promotes their survival by the JAK/STAT and Akt/NF-kappaB-dependent pathways. J Hepatol 51:139-48