The liver is particularly susceptible to the detrimental effects of a high fat diet (HFD), rapidly developing lipid accumulation and impaired cellular homeostasis. Recently, dietary nitrate has been shown to attenuate HFD-induced whole body glucose intolerance and liver steatosis, however the underlying mechanism(s) remain poorly defined. In the current study we investigated the ability of dietary nitrate to minimize possible impairments in liver mitochondrial bioenergetics following 8 wk of HFD (60% fat) in male C57BL/6J mice. Consumption of a HFD caused whole-body glucose intolerance (p<0.0001), and within the liver, increased lipid accumulation (p<0.0001), mitochondrial-specific reactive oxygen species emission (p=0.007), and markers of oxidative stress. Remarkably, dietary nitrate attenuated almost all of these pathological responses. Despite the reduction in lipid accumulation and redox stress (reduced TBARS and nitrotyrosine), nitrate did not improve insulin signaling within the liver or whole-body pyruvate tolerance (p=0.313 HFD vs HFD+nitrate). Moreover, the beneficial effects of nitrate were independent of changes in weight gain, 5' AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) signaling, mitochondrial content, mitochondrial respiratory capacity and ADP sensitivity or antioxidant protein content. Combined, these data suggest nitrate supplementation represents a potential therapeutic strategy to attenuate hepatic lipid accumulation and decrease mitochondrial ROS emission following HFD, processes linked to improvements in whole-body glucose tolerance. However, the beneficial effects of nitrate within the liver do not appear to be a result of increased oxidative capacity or mitochondrial substrate sensitivity.

中文翻译：

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独立于线粒体呼吸功能，饮食硝酸盐减弱肝内 HFD 诱导的脂质积累和线粒体 ROS 排放

肝脏特别容易受到高脂肪饮食 (HFD) 的不利影响、快速发展的脂质积累和受损的细胞稳态。最近，膳食硝酸盐已被证明可以减轻 HFD 引起的全身葡萄糖耐受不良和肝脏脂肪变性，但其潜在机制仍不清楚。在当前的研究中，我们研究了膳食硝酸盐在雄性 C57BL/6J 小鼠中 8 周 HFD（60% 脂肪）后最大限度地减少肝脏线粒体生物能量学可能受损的能力。食用 HFD 会导致全身葡萄糖不耐受 (p<0.0001)，并在肝脏内增加脂质积累 (p<0.0001)、线粒体特异性活性氧排放 (p=0.007) 和氧化应激标志物。值得注意的是，膳食硝酸盐几乎可以减弱所有这些病理反应。尽管减少了脂质积累和氧化还原应激（减少了 TBARS 和硝基酪氨酸），硝酸盐并没有改善肝脏内的胰岛素信号或全身丙酮酸耐受性（p=0.313 HFD vs HFD+硝酸盐）。此外，硝酸盐的有益作用与体重增加、5' AMP 活化蛋白激酶 (AMPK) 和乙酰辅酶 A 羧化酶 (ACC) 信号、线粒体含量、线粒体呼吸能力和 ADP 敏感性或抗氧化蛋白含量的变化无关。综合起来，这些数据表明硝酸盐补充剂代表了一种潜在的治疗策略，可减轻肝脂质积累并减少 HFD 后线粒体 ROS 的排放，这一过程与全身葡萄糖耐量的改善有关。然而，