Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction.

Autor:	Boland ML; Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States., Oldham S; Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States., Boland BB; Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States., Will S; Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States., Lapointe JM; Pathology, MedImmune Ltd., Cambridge CB21 6GH, United Kingdom., Guionaud S; Pathology, Drug Safety and Metabolism, IMED Biotech Unit, AstraZeneca, Cambridge CB22 3AT, United Kingdom., Rhodes CJ; Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States., Trevaskis JL; Cardiovascular and Metabolic Diseases, MedImmune LLC, Gaithersburg, MD 20878, United States. trevaskisj@medimmune.com.
Jazyk:	angličtina
Zdroj:	World journal of gastroenterology [World J Gastroenterol] 2018 Apr 28; Vol. 24 (16), pp. 1748-1765.
DOI:	10.3748/wjg.v24.i16.1748
Abstrakt:	Aim: To comprehensively evaluate mitochondrial (dys) function in preclinical models of nonalcoholic steatohepatitis (NASH). Methods: We utilized two readily available mouse models of nonalcoholic fatty liver disease (NAFLD) with or without progressive fibrosis: Lep ob /Lep ob ( ob/ob ) and FATZO mice on high trans -fat, high fructose and high cholesterol (AMLN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1 , Sod1 , Sod2 , catalase and 8-OHdG. Results: When challenged with AMLN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase (SOD) was increased in ob/ob AMLN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHdG, a marker of oxidative DNA damage, was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57BL6J control mice, but significantly perturbed in ob/ob mice. Conclusion: Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is a key factor for development of hepatic injury and fibrosis in these mouse models. Competing Interests: Conflict-of-interest statement: All authors are current employees and/or stockholders of MedImmune/AstraZeneca.
Databáze:	MEDLINE
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