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Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis
The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiolo...
Autores principales: | , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BlackWell Publishing Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448984/ https://www.ncbi.nlm.nih.gov/pubmed/26038701 http://dx.doi.org/10.1002/prp2.125 |
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author | de la Rosa, Laura Conde Vrenken, Titia E Buist-Homan, Manon Faber, Klaas Nico Moshage, Han |
author_facet | de la Rosa, Laura Conde Vrenken, Titia E Buist-Homan, Manon Faber, Klaas Nico Moshage, Han |
author_sort | de la Rosa, Laura Conde |
collection | PubMed |
description | The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiology of diabetes complications. Metformin has been shown to be hepatoprotective in the insulin-resistant and leptin-deficient ob/ob mouse model of NAFLD. However, the mechanism involved in the protective effects of metformin has not been elucidated yet. Therefore, we investigated the protective effect of metformin against oxidative stress-induced apoptosis. Primary rat hepatocytes were exposed to the oxidative stress-generating compound menadione in the presence and absence of metformin. Apoptosis was determined by measuring caspase activity and poly(ADP-ribose) polymerase (PARP)-cleavage, and necrosis was measured by Sytox Green nuclear staining. We demonstrate that (1) Metformin inhibits menadione-induced caspase-9,-6,-3 activation and PARP-cleavage in a concentration-dependent manner. (2) Metformin increases menadione-induced heme oxygenase-1 (HO-1) expression and inhibits c-Jun N-terminal kinase (JNK)-phosphorylation. (3) Metformin does not induce necrosis in primary hepatocytes. Metformin protects hepatocytes against oxidative stress-induced caspase activation, PARP-cleavage and apoptosis. The anti-apoptotic effect of metformin is in part dependent on HO-1 and bcl-xl induction and inhibition of JNK activation and independent of insulin signaling. Our results elucidate novel protective mechanisms of metformin and indicate that metformin could be investigated as a novel therapeutic agent for the treatment of oxidative stress-related liver diseases. |
format | Online Article Text |
id | pubmed-4448984 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | BlackWell Publishing Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-44489842015-06-02 Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis de la Rosa, Laura Conde Vrenken, Titia E Buist-Homan, Manon Faber, Klaas Nico Moshage, Han Pharmacol Res Perspect Original Articles The majority of chronic liver diseases are accompanied by oxidative stress, which induces apoptosis in hepatocytes and liver injury. Recent studies suggest that oxidative stress and insulin resistance are important in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and the pathophysiology of diabetes complications. Metformin has been shown to be hepatoprotective in the insulin-resistant and leptin-deficient ob/ob mouse model of NAFLD. However, the mechanism involved in the protective effects of metformin has not been elucidated yet. Therefore, we investigated the protective effect of metformin against oxidative stress-induced apoptosis. Primary rat hepatocytes were exposed to the oxidative stress-generating compound menadione in the presence and absence of metformin. Apoptosis was determined by measuring caspase activity and poly(ADP-ribose) polymerase (PARP)-cleavage, and necrosis was measured by Sytox Green nuclear staining. We demonstrate that (1) Metformin inhibits menadione-induced caspase-9,-6,-3 activation and PARP-cleavage in a concentration-dependent manner. (2) Metformin increases menadione-induced heme oxygenase-1 (HO-1) expression and inhibits c-Jun N-terminal kinase (JNK)-phosphorylation. (3) Metformin does not induce necrosis in primary hepatocytes. Metformin protects hepatocytes against oxidative stress-induced caspase activation, PARP-cleavage and apoptosis. The anti-apoptotic effect of metformin is in part dependent on HO-1 and bcl-xl induction and inhibition of JNK activation and independent of insulin signaling. Our results elucidate novel protective mechanisms of metformin and indicate that metformin could be investigated as a novel therapeutic agent for the treatment of oxidative stress-related liver diseases. BlackWell Publishing Ltd 2015-03 2015-03-18 /pmc/articles/PMC4448984/ /pubmed/26038701 http://dx.doi.org/10.1002/prp2.125 Text en © 2015 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics. http://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Original Articles de la Rosa, Laura Conde Vrenken, Titia E Buist-Homan, Manon Faber, Klaas Nico Moshage, Han Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
title | Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
title_full | Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
title_fullStr | Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
title_full_unstemmed | Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
title_short | Metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
title_sort | metformin protects primary rat hepatocytes against oxidative stress-induced apoptosis |
topic | Original Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4448984/ https://www.ncbi.nlm.nih.gov/pubmed/26038701 http://dx.doi.org/10.1002/prp2.125 |
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