Up-regulation of nerve growth factor in cholestatic livers and its hepatoprotective role against oxidative stress.
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.
Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan; The School of Medicine for Post-Baccalaureate, I-Shou University, Kaohsiung, Taiwan.
Ming-Shian
MS
Tsai
Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
Yu-Chun
YC
Lin
Department of Medical Education, E-DA Hospital, Kaohsiung, Taiwan.
Cheuk-Kwan
CK
Sun
Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
Shih-Che
SC
Huang
Department of Surgery, E-DA Hospital, Kaohsiung, Taiwan; Department of Surgery, National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.
Po-Huang
PH
Lee
Department of Medical Research, E-DA Hospital, Kaohsiung, Taiwan.
Ying-Hsien
YH
Kao
D000818:Animals; D001652:Bile Ducts / Q000601:surgery; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002779:Cholestasis / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007249:Inflammation / Q000473:pathology; D008026:Ligation; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008775:Methylprednisolone / Q000494:pharmacology; D008813:Mice, Inbred ICR; D020932:Nerve Growth Factor / Q000097:blood / Q000378:metabolism*; D018384:Oxidative Stress / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D020011:Protective Agents / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011916:Rats, Inbred F344; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000378:metabolism
D020011:Protective Agents; D053773:Transforming Growth Factor beta1; D051028:bcl-2-Associated X Protein; D020932:Nerve Growth Factor; D006861:Hydrogen Peroxide; D051057:Proto-Oncogene Proteins c-akt; D008775:Methylprednisolone