1. Up-regulation of nerve growth factor in cholestatic livers and its hepatoprotective role against oxidative stress.
- Author
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Tsai MS, Lin YC, Sun CK, Huang SC, Lee PH, and Kao YH
- Subjects
- Animals, Bile Ducts surgery, Cell Death drug effects, Cells, Cultured, Cholestasis blood, Hepatocytes drug effects, Hepatocytes metabolism, Hepatocytes pathology, Humans, Hydrogen Peroxide pharmacology, Inflammation pathology, Ligation, Liver drug effects, Liver pathology, Male, Methylprednisolone pharmacology, Mice, Inbred ICR, Nerve Growth Factor blood, Phosphorylation drug effects, Proto-Oncogene Proteins c-akt metabolism, Rats, Inbred F344, Transforming Growth Factor beta1 metabolism, bcl-2-Associated X Protein metabolism, Cholestasis metabolism, Cholestasis pathology, Liver metabolism, Nerve Growth Factor metabolism, Oxidative Stress drug effects, Protective Agents metabolism, Up-Regulation drug effects
- 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.
- Published
- 2014
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