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 #
5R01DK083283-04
Application #
8433381
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Doo, Edward
Project Start
2010-03-20
Project End
2015-02-28
Budget Start
2013-03-01
Budget End
2014-02-28
Support Year
4
Fiscal Year
2013
Total Cost
$299,341
Indirect Cost
$101,106
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
Tepper, Clifford G; Dang, Julie H T; Stewart, Susan L et al. (2018) High frequency of the PNPLA3 rs738409 [G] single-nucleotide polymorphism in Hmong individuals as a potential basis for a predisposition to chronic liver disease. Cancer 124 Suppl 7:1583-1589
Matsumoto, Misaki; Zhang, Jia; Zhang, Xueqing et al. (2018) The NOX1 isoform of NADPH oxidase is involved in dysfunction of liver sinusoids in nonalcoholic fatty liver disease. Free Radic Biol Med 115:412-420
Ouyang, Xinshou; Han, Sheng-Na; Zhang, Ji-Yuan et al. (2018) Digoxin Suppresses Pyruvate Kinase M2-Promoted HIF-1? Transactivation in Steatohepatitis. Cell Metab 27:1156
Torok, Natalie J (2018) P300, A New Player in Mechanosensitivity and Activation of Cancer-Associated Fibroblasts. Gastroenterology 154:2025-2026
Zhou, Zhou; Xu, Ming-Jiang; Cai, Yan et al. (2018) Neutrophil-Hepatic Stellate Cell Interactions Promote Fibrosis in Experimental Steatohepatitis. Cell Mol Gastroenterol Hepatol 5:399-413
Sasaki, Yu; Dehnad, Ali; Fish, Sarah et al. (2017) NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease. Sci Rep 7:46144
Török, Natalie J (2017) TRIF as a Novel Modulator of Liver Inflammation and Fibrosis. Cell Mol Gastroenterol Hepatol 3:299-300
Tian, Jijing; Yang, Guoxiang; Chen, Huan-Yuan et al. (2016) Galectin-3 regulates inflammasome activation in cholestatic liver injury. FASEB J 30:4202-4213
Török, Natalie J (2016) Extracellular vesicles and ceramide: new mediators for macrophage chemotaxis? J Lipid Res 57:157-8
Haque, Amranul; Gheibi, Pantea; Stybayeva, Gulnaz et al. (2016) Ductular reaction-on-a-chip: Microfluidic co-cultures to study stem cell fate selection during liver injury. Sci Rep 6:36077

Showing the most recent 10 out of 24 publications