PDF(Pubmed)
Abstract：
Exercise as a lifestyle modification is a frontline therapy for nonalcoholic fatty liver disease (NAFLD), but how components of exercise attenuate steatosis is unclear. To uncouple the effect of increased muscle mass from weight loss in obesity, myostatin knockout mice were bred on a lean and obese db/db background. Myostatin deletion increases gastrocnemius (Gastrocn.) mass and reduces hepatic steatosis and hepatic sterol regulatory element binding protein 1 (Srebp1) expression in obese mice, with no impact on adiposity or body weight. Interestingly, hypermuscularity reduces hepatic NADPH oxidase 1 (Nox1) expression but not NADPH oxidase 4 (Nox4) in db/db mice. To evaluate a deterministic function of Nox1 on steatosis, Nox1 knockout mice were bred on a lean and db/db background. NOX1 deletion significantly attenuates hepatic oxidant stress, steatosis, and Srebp1 programming in obese mice to parallel hypermuscularity, with no improvement in adiposity, glucose control, or hypertriglyceridemia to suggest off-target effects. Directly assessing the role of NOX1 on SREBP1, insulin (Ins)-mediated SREBP1 expression was significantly increased in either NOX1, NADPH oxidase organizer 1 (NOXO1), and NADPH oxidase activator 1 (NOXA1) or NOX5-transfected HepG2 cells versus ?-galactosidase control virus, indicating superoxide is the key mechanistic agent for the actions of NOX1 on SREBP1. Metabolic Nox1 regulators were evaluated using physiological, genetic, and diet-induced animal models that modulated upstream glucose and insulin signaling, identifying hyperinsulinemia as the key metabolic derangement explaining Nox1-induced steatosis in obesity. GEO data revealed that hepatic NOX1 predicts steatosis in obese humans with biopsy-proven NAFLD. Taken together, these data suggest that hypermuscularity attenuates Srebp1 expression in db/db mice through a NOX1-dependent mechanism.NEW & NOTEWORTHY This study documents a novel mechanism by which changes in body composition, notably increased muscle mass, protect against fatty liver disease. This mechanism involves NADPH oxidase 1 (NOX1), an enzyme that increases superoxide and increases insulin signaling, leading to increased fat accumulation in the liver. NOX1 may represent a new early target for preventing fatty liver to stave off later liver diseases such as cirrhosis or liver cancer.
摘要：
背景与目的：运动作为一种生活方式的改变是NAFLD的一线治疗，但运动成分如何减轻脂肪变性尚不清楚。方法和结果：为了消除肥胖中肌肉质量增加与体重减轻的影响，肌肉生长抑制素敲除小鼠在瘦和肥胖db/db背景下饲养。肌肉生长抑制素缺失增加腓肠肌质量，减少肥胖小鼠的肝脏脂肪变性和肝脏Srebp1表达，对肥胖或体重没有影响。有趣的是,高肌肉减少肝NADPH氧化酶1（Nox1）表达，但不是Nox4，在db/db小鼠中。为了评估Nox1对脂肪变性的确定性功能，Nox1敲除小鼠在瘦和db/db背景下饲养。NOX1缺失显著减弱肝脏氧化应激，脂肪变性,和Srebp1在肥胖小鼠中编程为平行的高肌肉，肥胖没有改善，血糖控制,或高甘油三酯血症提示脱靶效应。直接评估NOX1对SREBP1的作用，胰岛素介导的SREBP1表达在NOX1，NOXO1和NOXA1或NOX5转染的HepG2细胞中与β-半乳糖苷酶对照病毒相比显着增加，表明超氧化物是NOX1对SREBP1作用的关键机制剂。代谢Nox1调节剂使用生理，遗传,和饮食诱导的动物模型，调节上游葡萄糖和胰岛素信号，确定高胰岛素血症是解释肥胖中Nox1诱导的脂肪变性的关键代谢紊乱。GEO数据显示，肝NOX1可预测活检证实的NAFLD肥胖人群的脂肪变性。结论：综合来看，这些数据表明,高肌肉通过NOX1依赖性机制减弱db/db小鼠中Srebp1的表达.
