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| 1 | Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction显示文摘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-OHd G, 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 C57 BL6 J 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. | Michelle L Boland Stephanie Oldham Brandon B Boland Sarah Will Jean-Martin Lapointe Silvia Guionaud Christopher J Rhodes James L Trevaskis | 2018 | World Journal of Gastroenterology2018，24，16： | 7 |
| 2 | Two hemoglobin genes in Arabidopsis thaliana : the evolutionary origins of leghemoglobins显示文摘 | TREVASKIS B WATTS R A ANDERSSON C R | 1997 | Proc Natl Acad Sci USA1997，94，12： | 1 |
| 3 | Increased level of hemoglobin 1 enhances survival of hypoxie stress and promotes early growth in Arabidopsis thaliana 显示文摘 | HUNT P W KLOK E J TREVASKIS B | 2002 | Proc Natl Acad Sci USA2002，99，17： | 1 |
| 4 | Short vegetative phase-like MADS-box genes inhibit floral meristem identity in barley显示文摘 | TREVASKIS B TADEGE M HEMMING M N | 2007 | Plant Physiol2007，143，1： | 1 |
| 5 | Expression and evolution of functionally distinct haemoglobin genes in plants 显示文摘 | HUNT P W WATTS R A TREVASKIS B | 2001 | Plant Mol Biol2001，47，5： | 1 |
| 6 | Two hemoglobin genes in Arabidopsis thaliana: The evolutionary o- rigins of leghemoglobins 显示文摘 | TREVASKIS B WATTS R A ANDERSSON C R | 1997 | Proc Natl Acad Sci U S A1997，94，12： | 1 |
| 7 | Molecular and cell biology of a family of voltage-dependentan ion chan- nel porins in Lotus japonicus 显示文摘 | WANDREY M TREVASKIS B BREWIN N | 2004 | Plant Physiol2004，134，1： | 1 |
| 8 | MADS box genes control vernalization-induced flowering in cereals 显示文摘 | TREVASKIS B BAGNALL D ELLIS M | 2003 | PNAS2003，100，13： | 1 |
| 9 | Make hay when the sun shines:The role of MADS-box genes in temperature-de- pendant seasonal flowering responses 显示文摘 | Hemming M N Trevaskis B | 2011 | Plant Science2011，180，3： | 1 |
| 10 | MADS box genes control vernalization-induced flowering in cereals 显示文摘 | Trevaskis B Bagnall D J Ellis M H | 2003 | Proceedings of the National Academy of Sciences2003，100，13： | 1 |
| 11 | Short vegetative phase-like MADS-box Genes inhibit floral meristem identity in barley显示文摘 | Trevaskis B Tadege M Hemming MN | 2000 | Plant Physiology2000，143，： | 1 |
| 12 | Make hay when the sun shinestlm role of MAIX%box genes in lernperaturedependant seanal flowering resfxmses 显示文摘 | HEMMING M N TREVASKIS B | 2011 | Plant Science2011，180，： | 1 |
| 13 | Short vegetative phase-like MADS-box genes inhibit floral meristem identity in barley显示文摘 | Trevaskis B Tadege M Hemming MN | 2007 | Plant Physiology2007，143，1： | 1 |
| 14 | Short Vegetative Phase-Like MADS-box genes inhibit floral meristem identity in Barley显示文摘 | TREVASKIS B TADEGE M MEGAN N | 2007 | Plant Physiology2007，143，： | 1 |
| 15 | Two hemoglobin genes in Arabidopsis thaliana: the evolutionary origins of leghemoglobins 显示文摘 | TREVASKIS B WATTS RA ANDERSSON CR 1997 | 1997 | Proc Natl Acad Sci USA1997，94，12： | 1 |
| 16 | Symbiotic nitrogen fixation research in the post-genomic era 显示文摘 | Colebatch G Trevaskis B Udvardi M | 2002 | New Phytol2002，153，： | 1 |
| 17 | Role of adiponectin and inflammation in insulin resistance of mc3r and mc4r knockout mice 显示文摘 | Trevaskis JL Gawronska- Kozak B Sutton GM | 2007 | Obesity (Silver Spring)2007，15，11： | 1 |
| 18 | Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice显示文摘 | TREVASKIS JL GAWRONSKA-KOZAK B SUTrON GM | 2007 | Obesity2007，15，11： | 1 |
| 19 | The molecular basis of vernalization-induced flowering in cereals显示文摘 | Trevaskis B Hemming MN Dennis ES | 2007 | Trends Plant Sci2007，12，： | 1 |
| 20 | MADS box genes control vernalization-induced flowering in cereals显示文摘 | Trevaskis B Bagnall D J Dennis E S | 2003 | Proceedings of the National Academy of Sciences2003，100，23： | 1 |
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