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...
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2018-01-01
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Series: | International Journal of Hepatology |
Online Access: | http://dx.doi.org/10.1155/2018/3484107 |
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doaj-2f59c4d9df324c50bc6b0e37fe9efbad2020-11-25T01:56:01ZengHindawi LimitedInternational Journal of Hepatology2090-34482090-34562018-01-01201810.1155/2018/34841073484107Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative StressDavid Sacerdoti0Shailendra P. Singh1Joseph Schragenheim2Lars Bellner3Luca Vanella4Marco Raffaele5Aliza Meissner6Ilana Grant7Gaia Favero8Rita Rezzani9Luigi F. Rodella10David Bamshad11Edward Lebovics12Nader G. Abraham13Departments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartment of Drug Science, University of Catania, Catania, ItalyDepartment of Drug Science, University of Catania, Catania, ItalyDepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USAAnatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalyAnatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalyAnatomy and Physiopathology Division, Department of Clinical and Experimental Sciences, University of Brescia, Brescia, ItalyDepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USADepartments of Medicine, Pharmacology and Gastroenterology, New York Medical College, Valhalla, NY 10595, USAAim. 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.http://dx.doi.org/10.1155/2018/3484107 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
David Sacerdoti Shailendra P. Singh Joseph Schragenheim Lars Bellner Luca Vanella Marco Raffaele Aliza Meissner Ilana Grant Gaia Favero Rita Rezzani Luigi F. Rodella David Bamshad Edward Lebovics Nader G. Abraham |
spellingShingle |
David Sacerdoti Shailendra P. Singh Joseph Schragenheim Lars Bellner Luca Vanella Marco Raffaele Aliza Meissner Ilana Grant Gaia Favero Rita Rezzani Luigi F. Rodella David Bamshad Edward Lebovics Nader G. Abraham Development of NASH in Obese Mice is Confounded by Adipose Tissue Increase in Inflammatory NOV and Oxidative Stress International Journal of Hepatology |
author_facet |
David Sacerdoti Shailendra P. Singh Joseph Schragenheim Lars Bellner Luca Vanella Marco Raffaele Aliza Meissner Ilana Grant Gaia Favero Rita Rezzani Luigi F. Rodella David Bamshad Edward Lebovics Nader G. Abraham |
author_sort |
David Sacerdoti |
title |
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_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_sort |
development of nash in obese mice is confounded by adipose tissue increase in inflammatory nov and oxidative stress |
publisher |
Hindawi Limited |
series |
International Journal of Hepatology |
issn |
2090-3448 2090-3456 |
publishDate |
2018-01-01 |
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. |
url |
http://dx.doi.org/10.1155/2018/3484107 |
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