Nerve growth factor upregulates sirtuin 1 expression in cholestasis: a potential therapeutic target
Autor: | Ting-Chia Chiu, Po-Han Chen, Ming-Shian Tsai, Yu-Chun Lin, Po-Huang Lee, I-Wei Chang, Cheuk-Kwan Sun, Ying-Hsien Kao |
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Jazyk: | angličtina |
Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Male Programmed cell death medicine.medical_specialty Carcinoma Hepatocellular Clinical Biochemistry Nerve Tissue Proteins Receptors Nerve Growth Factor Tropomyosin receptor kinase A Biochemistry Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Sirtuin 1 Internal medicine Nerve Growth Factor medicine Animals Humans Protein Precursors Receptor trkA Receptor Molecular Biology Protein kinase B Liver injury Mice Inbred ICR Cholestasis biology Chemistry Liver Neoplasms medicine.disease Up-Regulation 030104 developmental biology Nerve growth factor Endocrinology nervous system 030220 oncology & carcinogenesis biology.protein Molecular Medicine Original Article Bile Ducts |
Zdroj: | Experimental & Molecular Medicine |
ISSN: | 2092-6413 1226-3613 |
Popis: | This study investigated the regulatory role of nerve growth factor (NGF) in sirtuin 1 (SIRT1) expression in cholestatic livers. We evaluated the expression of NGF and its cognate receptors in human livers with hepatolithiasis and the effects of NGF therapy on liver injury and hepatic SIRT1 expression in a bile duct ligation (BDL) mouse model. Histopathological and molecular analyses showed that the hepatocytes of human diseased livers expressed NGF, proNGF (a precursor of NGF), TrkA and p75NTR, whereas only p75NTR was upregulated in hepatolithiasis, compared with non-hepatolithiasis livers. In the BDL model without NGF therapy, p75NTR, but not TrkA antagonism, significantly deteriorated BDL-induced liver injury. By contrast, the hepatoprotective effect of NGF was abrogated only by TrkA and not by p75NTR antagonism in animals receiving NGF therapy. Intriguingly, a positive correlation between hepatic SIRT1 and NGF expression was found in human livers. In vitro studies demonstrated that NGF upregulated SIRT1 expression in mouse livers and human Huh-7 and rodent hepatocytes. Both NGF and proNGF induced protective effects against hydrogen peroxide-induced cytotoxicity in Huh-7 cells, whereas inhibition of TrkA and p75NTR activity prevented oxidative cell death. Mechanistically, NGF, but not proNGF, upregulated SIRT1 expression in human Huh-7 and rodent hepatocytes via nuclear factor (NF)-κB activity, whereas NGF-induced phosphoinositide-3 kinase/Akt, extracellular signal-regulated kinase and NF-κB signaling and SIRT1 activity were involved in its hepatoprotective effects against oxidative injury. These findings suggest that pharmacological manipulation of the NGF/SIRT1 axis might serve as a novel approach for the treatment of cholestatic disease. |
Databáze: | OpenAIRE |
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