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Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress
AIM: Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, result...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Hindawi
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051135/ https://www.ncbi.nlm.nih.gov/pubmed/30057822 http://dx.doi.org/10.1155/2018/3484107 |
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author | Sacerdoti, David Singh, Shailendra P. Schragenheim, Joseph Bellner, Lars Vanella, Luca Raffaele, Marco Meissner, Aliza Grant, Ilana Favero, Gaia Rezzani, Rita Rodella, Luigi F. Bamshad, David Lebovics, Edward Abraham, Nader G. |
author_facet | Sacerdoti, David Singh, Shailendra P. Schragenheim, Joseph Bellner, Lars Vanella, Luca Raffaele, Marco Meissner, Aliza Grant, Ilana Favero, Gaia Rezzani, Rita Rodella, Luigi F. Bamshad, David Lebovics, Edward Abraham, Nader G. |
author_sort | Sacerdoti, David |
collection | PubMed |
description | AIM: Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. METHODS: Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. RESULTS: NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. CONCLUSIONS: These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH. |
format | Online Article Text |
id | pubmed-6051135 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | Hindawi |
record_format | MEDLINE/PubMed |
spelling | pubmed-60511352018-07-29 Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress Sacerdoti, David Singh, Shailendra P. Schragenheim, Joseph Bellner, Lars Vanella, Luca Raffaele, Marco Meissner, Aliza Grant, Ilana Favero, Gaia Rezzani, Rita Rodella, Luigi F. Bamshad, David Lebovics, Edward Abraham, Nader G. Int J Hepatol Research Article AIM: Nonalcoholic steatohepatitis (NASH) is the consequence of insulin resistance, fatty acid accumulation, oxidative stress, and lipotoxicity. We hypothesize that an increase in the inflammatory adipokine NOV decreases antioxidant Heme Oxygenase 1 (HO-1) levels in adipose and hepatic tissue, resulting in the development of NASH in obese mice. METHODS: Mice were fed a high fat diet (HFD) and obese animals were administered an HO-1 inducer with or without an inhibitor of HO activity to examine levels of adipose-derived NOV and possible links between increased synthesis of inflammatory adipokines and hepatic pathology. RESULTS: NASH mice displayed decreased HO-1 levels and HO activity, increased levels of hepatic heme, NOV, MMP2, hepcidin, and increased NAS scores and hepatic fibrosis. Increased HO-1 levels are associated with a decrease in NOV, improved hepatic NAS score, ameliorated fibrosis, and increases in mitochondrial integrity and insulin receptor phosphorylation. Adipose tissue function is disrupted in obesity as evidenced by an increase in proinflammatory molecules such as NOV and a decrease in adiponectin. Importantly, increased HO-1 levels are associated with a decrease of NOV, increased adiponectin levels, and increased levels of thermogenic and mitochondrial signaling associated genes in adipose tissue. CONCLUSIONS: These results suggest that the metabolic abnormalities in NASH are driven by decreased levels of hepatic HO-1 that is associated with an increase in the adipose-derived proinflammatory adipokine NOV in our obese mouse model of NASH. Concurrently, induction of HO-1 provides protection against insulin resistance as seen by increased insulin receptor phosphorylation. Pharmacological increases in HO-1 associated with decreases in NOV may offer a potential therapeutic approach in preventing fibrosis, mitochondrial dysfunction, and the development of NASH. Hindawi 2018-07-02 /pmc/articles/PMC6051135/ /pubmed/30057822 http://dx.doi.org/10.1155/2018/3484107 Text en Copyright © 2018 David Sacerdoti et al. https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Research Article Sacerdoti, David Singh, Shailendra P. Schragenheim, Joseph Bellner, Lars Vanella, Luca Raffaele, Marco Meissner, Aliza Grant, Ilana Favero, Gaia Rezzani, Rita Rodella, Luigi F. Bamshad, David Lebovics, Edward Abraham, Nader G. Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress |
title | Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress |
title_full | Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress |
title_fullStr | Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress |
title_full_unstemmed | Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress |
title_short | Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress |
title_sort | development of nash in obese mice is confounded by adipose tissue increase in inflammatory nov and oxidative stress |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051135/ https://www.ncbi.nlm.nih.gov/pubmed/30057822 http://dx.doi.org/10.1155/2018/3484107 |
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