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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 | Artificial neural networks in process esitmation and control显示文摘 | M J Wills G A Montague | 1992 | Automatica1992，28，6： | 2 |
| 3 | Fabrica tion of thin electrolytes for second-generation solid oxide fuel cells 显示文摘 | WILL J MITTERDORFER A KLEINLOGEL C | 2000 | Solid State Ionics2000，131，： | 2 |
| 4 | Sensidvity to choli-nevgic drug treatments of aged rats with variable degrees of spatial memory impairment显示文摘 | Stemmelin J Cassel JC Will B | 1999 | Behav Brain Res1999，98，： | 1 |
| 5 | Decision framework for chemotherapeutic interventions for metastatic non-small-cell lung cancer显示文摘 | Berthelot J M Will B P Evans W K | 2000 | J Natl Cancer Inst2000，92，16： | 1 |
| 6 | Familial myopathy with tubular aggregates associated with abnormal pupils显示文摘 | Shahrizaila N Lowe J Wills A | 2004 | Neurology2004，63，6： | 1 |
| 7 | Duration of infection and proportion of pigs persistently infected with porcine reproductive and respiratory syndrome virus显示文摘 | Wills R W Doster A R Galeota J A | 2003 | J Clin Microbiol2003，41，1： | 1 |
| 8 | Prostate cancer cells with stem cellcharacteristics reconstitute the original human tumor in vivo显示文摘 | Gu G Yuan J Wills M | 2007 | Cancer Res2007，67，10： | 1 |
| 9 | Burnout and self-effi-cacy: A study on teachers'''' beliefswhen implementing an innovative edu-caitonal system in the Netherlands显示文摘 | Will J G Evers Andre Brouwers Welko Tomic | | 0，，06： | 1 |
| 10 | Valuing informal recreation on the forestry commission estate显示文摘 | Benson J F、Wills K G | 1993 | Quarterly Journal of Forestry1993，16，3： | 1 |
| 11 | Functional selectivity for glycerol of the nodulin 26 subfamily of plant membrane intrinsic proteins显示文摘 | Wallace I S Wills D M Guenther J F | 2002 | FEBS Lett2002，523，： | 1 |
| 12 | Screening for microorganisms producing D-malate from maleate显示文摘 | Will JJ van den Tweel Sybe Hartmans | 1993 | Appl Environ Microbiol1993，58，： | 1 |
| 13 | Treatment of a-cute intracranial vertebrobasilar dissection with angioplasty and stent placement:report of two cases显示文摘 | Willing SJ Skidmore F Donaldson J | 2003 | Am J Neuro-radiol2003，24，： | 1 |
| 14 | Selection against frameshift mutations limits microsatellite expansion in coding DNA 显示文摘 | METZGAR D BYTOF J WILLS C | 2000 | Genome Res2000，10，： | 1 |
| 15 | Total-energy study of electronic structure and mechanical behavior of C15 Laves phase compounds:NbCr2 and HfV2显示文摘 | Ormeci A Chu F Wills J M | 1996 | Physical Review B1996，54，12： | 1 |
| 16 | Inter-company comparison using modified TOPSIS with objective weights显示文摘 | Wills R J | 2000 | Computers & Operations Research2000，27，10： | 1 |
| 17 | Retinol administration to superovulated ewes improves in vitro embryonic viability显示文摘 | Eberhardt D M Will W A Godkin J D | 1999 | Biology of Reproduction1999，60，： | 1 |
| 18 | Hair removal policies in clean surgery: systematic review of randomized, controlled trials 显示文摘 | NIEL-WEISE B S WILLE J C VAN DEN BROEK P J | 2005 | Infec Control Hosp Epidemiol2005，26，12： | 1 |
| 19 | Humidifi- cation policies for mechanically ventilated intensive care patients and prevention of ventilator-associated pneumo- nia: a systematic review of randomized controlled trials 显示文摘 | Nil-Weise B S Wille J C van den Broek P J | 2007 | J Hosp Infect2007，65，4： | 1 |
| 20 | Analysis of mitochondrial function using phosphorescent oxygen- sensitive probes显示文摘 | WILL Y HYNES J OGURTSOV VI et 0l | 2006 | Nat Protoe2006，1，6： | 1 |
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