Up-regulation of nerve growth factor in cholestatic livers and its hepatoprotective role against oxidative stress
Journal
PLoS ONE
Journal Volume
9
Journal Issue
11
Pages
e112113
Date Issued
2014
Author(s)
Abstract
The role of nerve growth factor (NGF) in liver injury induced by bile duct ligation (BDL) remains elusive. This study aimed to investigate the relationship between inflammation and hepatic NGF expression, to explore the possible upstream molecules up-regulating NGF, and to determine whether NGF could protect hepatocytes from oxidative liver injury. Biochemical and molecular detection showed that NGF was up-regulated in cholestatic livers and plasma, and well correlated with systemic and hepatic inflammation. Conversely, systemic immunosuppression reduced serum NGF levels and resulted in higher mortality in BDL-treated mice. Immunohistochemistry showed that the up-regulated NGF was mainly localized in parenchymal hepatocytes. In vitro mechanistic study further demonstrated that TGF-β1 up-regulated NGF expression in clone-9 and primary rat hepatocytes. Exogenous NGF supplementation and endogenous NGF overexpression effectively protected hepatocytes against TGF-β1- and oxidative stress-induced cell death in vitro, along with reduced formation of oxidative adducted proteins modified by 4-HNE and 8-OHdG. TUNEL staining confirmed the involvement of anti-apoptosis in the NGF-exhibited hepatoprotection. Moreover, NGF potently induced Akt phosphorylation and increased Bcl-2 to Bax ratios, whereas these molecular alterations by NGF were only seen in the H2O2-, but not TGF-β1-treated hepatocytes. In conclusion, NGF exhibits anti-oxidative and hepatoprotective effects and is suggested to be therapeutically applicable in treating cholestatic liver diseases. Copyright: ? 2014 Tsai et al.
SDGs
Other Subjects
4 hydroxynonenal; 8 hydroxydeoxyguanosine; hydrogen peroxide; interleukin 6; methylprednisolone sodium succinate; nerve growth factor; protein Bax; protein bcl 2; protein kinase B; transforming growth factor beta1; tumor necrosis factor alpha; hydrogen peroxide; methylprednisolone; nerve growth factor; protective agent; protein Bax; protein kinase B; transforming growth factor beta1; animal cell; animal experiment; animal model; animal tissue; Article; bile duct ligation; cell death; cell protection; cellular distribution; controlled study; correlational study; gene overexpression; hepatitis; IL 6 gene; immune deficiency; immunohistochemistry; in vitro study; intrahepatic cholestasis; liver cell; liver protection; liver toxicity; male; mouse; NGF gene; nick end labeling; nonhuman; oxidative stress; protein blood level; protein expression; protein function; protein phosphorylation; TGF b1 gene; TNF alpha gene; upregulation; animal; bile duct; blood; cell culture; cholestasis; drug effects; Fischer 344 rat; human; inflammation; Institute for Cancer Research mouse; ligation; liver; metabolism; pathology; phosphorylation; surgery; Animals; bcl-2-Associated X Protein; Bile Ducts; Cell Death; Cells, Cultured; Cholestasis; Hepatocytes; Humans; Hydrogen Peroxide; Inflammation; Ligation; Liver; Male; Methylprednisolone; Mice, Inbred ICR; Nerve Growth Factor; Oxidative Stress; Phosphorylation; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Inbred F344; Transforming Growth Factor beta1; Up-Regulation
Publisher
Public Library of Science
Type
journal article