Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis
Non-alcoholic fatty liver disease (NAFLD) is linked to obesity and insulin resistance and is the most prevalent chronic liver disease. During the development of obesity and NAFLD, mitochondria adapt to the increased lipid load in hepatocytes by increasing the rate of fatty acid oxidation. In concert...
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doaj-e1d75d6d9b8f48a39368b51bd0c7e0f52020-11-25T02:14:44ZengElsevierRedox Biology2213-23172019-04-0122Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosisNicholas K.H. Khoo0Marco Fazzari1Dionysios V. Chartoumpekis2Lihua Li3Danielle Aparecida Guimaraes4Gavin E. Arteel5Sruti Shiva6Bruce A. Freeman7Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Corresponding authors at: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsbrugh, PA 15261, United States.Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Fondazione Ri.MED, Via Bandiera 11, 90133 Palermo, ItalyDepartment of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United StatesDepartment of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United StatesVascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, United StatesDivision of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh, Pittsburgh, PA 15261, United StatesDepartment of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, United StatesDepartment of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsburgh, PA 15261, United States; Vascular Medicine Institute, University of Pittsburgh, Pittsburgh, PA 15261, United States; Corresponding authors at: Department of Pharmacology & Chemical Biology, University of Pittsburgh, Pittsbrugh, PA 15261, United States.Non-alcoholic fatty liver disease (NAFLD) is linked to obesity and insulin resistance and is the most prevalent chronic liver disease. During the development of obesity and NAFLD, mitochondria adapt to the increased lipid load in hepatocytes by increasing the rate of fatty acid oxidation. In concert with this, reactive species (RS) generation is increased, damaging hepatocytes and inducing inflammation. Hepatic mitochondrial dysfunction is central to the pathogenesis of NAFLD via undefined mechanisms. There are no FDA approved treatments for NAFLD other than weight loss and management of glucose tolerance. Electrophilic nitro-oleic acid (NO2-OA) displays anti-inflammatory and antioxidant signaling actions, thus mitochondrial dysfunction, RS production and inflammatory responses to NO2-OA and the insulin sensitizer rosiglitazone were evaluated in a murine model of insulin resistance and NAFLD. Mice on HFD for 20 wk displayed increased adiposity, insulin resistance and hepatic lipid accumulation (steatosis) compared to mice on normal chow (NC). The HFD mice had mitochondrial dysfunction characterized by lower hepatic mitochondrial complex I, IV and V activity compared to mice on NC. Treatment with NO2-OA or rosiglitazone for the last 42 days (out of 20 wk) abrogated HFD-mediated decreases in hepatic mitochondrial complex I, IV and V activity. Notably, NO2-OA treatment normalized hepatic triglyceride levels and significantly reversed hepatic steatosis. Despite the improved glucose tolerance observed upon rosiglitazone treatment, liver weight and hepatic triglycerides were significantly increased over vehicle-treated HFD mice. These observations support that the pleiotropic signaling actions of electrophilic fatty acids limit the complex hepatic and systemic pathogenic responses instigated by obesity, without the adverse effects of thiazolidinedione drugs such as rosiglitazone.http://www.sciencedirect.com/science/article/pii/S2213231718312515 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Nicholas K.H. Khoo Marco Fazzari Dionysios V. Chartoumpekis Lihua Li Danielle Aparecida Guimaraes Gavin E. Arteel Sruti Shiva Bruce A. Freeman |
spellingShingle |
Nicholas K.H. Khoo Marco Fazzari Dionysios V. Chartoumpekis Lihua Li Danielle Aparecida Guimaraes Gavin E. Arteel Sruti Shiva Bruce A. Freeman Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis Redox Biology |
author_facet |
Nicholas K.H. Khoo Marco Fazzari Dionysios V. Chartoumpekis Lihua Li Danielle Aparecida Guimaraes Gavin E. Arteel Sruti Shiva Bruce A. Freeman |
author_sort |
Nicholas K.H. Khoo |
title |
Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis |
title_short |
Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis |
title_full |
Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis |
title_fullStr |
Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis |
title_full_unstemmed |
Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis |
title_sort |
electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis |
publisher |
Elsevier |
series |
Redox Biology |
issn |
2213-2317 |
publishDate |
2019-04-01 |
description |
Non-alcoholic fatty liver disease (NAFLD) is linked to obesity and insulin resistance and is the most prevalent chronic liver disease. During the development of obesity and NAFLD, mitochondria adapt to the increased lipid load in hepatocytes by increasing the rate of fatty acid oxidation. In concert with this, reactive species (RS) generation is increased, damaging hepatocytes and inducing inflammation. Hepatic mitochondrial dysfunction is central to the pathogenesis of NAFLD via undefined mechanisms. There are no FDA approved treatments for NAFLD other than weight loss and management of glucose tolerance. Electrophilic nitro-oleic acid (NO2-OA) displays anti-inflammatory and antioxidant signaling actions, thus mitochondrial dysfunction, RS production and inflammatory responses to NO2-OA and the insulin sensitizer rosiglitazone were evaluated in a murine model of insulin resistance and NAFLD. Mice on HFD for 20 wk displayed increased adiposity, insulin resistance and hepatic lipid accumulation (steatosis) compared to mice on normal chow (NC). The HFD mice had mitochondrial dysfunction characterized by lower hepatic mitochondrial complex I, IV and V activity compared to mice on NC. Treatment with NO2-OA or rosiglitazone for the last 42 days (out of 20 wk) abrogated HFD-mediated decreases in hepatic mitochondrial complex I, IV and V activity. Notably, NO2-OA treatment normalized hepatic triglyceride levels and significantly reversed hepatic steatosis. Despite the improved glucose tolerance observed upon rosiglitazone treatment, liver weight and hepatic triglycerides were significantly increased over vehicle-treated HFD mice. These observations support that the pleiotropic signaling actions of electrophilic fatty acids limit the complex hepatic and systemic pathogenic responses instigated by obesity, without the adverse effects of thiazolidinedione drugs such as rosiglitazone. |
url |
http://www.sciencedirect.com/science/article/pii/S2213231718312515 |
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