Hepatic eNOS and Mitochondrial Function in NASH

非酒精性脂肪性肝病(NAFLD)包括一系列肝脏病理，从单纯性脂肪变性到 非酒精性脂肪性肝炎(NASH；肝脏炎症和纤维化)和肝硬变。非酒精性脂肪肝的影响更大 超过美国成年总人口的30%，令人不安的是，NAFLD和NASH的患病率 在军队和退伍军人中做得更好。NASH与肝脏相关疾病的增加直接相关， 心血管疾病和全因死亡率，以及肝移植的必要性。以前的研究 来自我们小组和其他人的研究表明，线粒体功能障碍与NASH的发展和 进步。不幸的是，调节肝脏线粒体功能的机制(S)增加了 对NASH的易感性在很大程度上是未知的。我们的团队最近证明了正常的内皮细胞 一氧化氮合酶(ENOS)活性在肥胖大鼠向NASH转变过程中丢失，并且 全身性一氧化氮合酶抑制导致肝脏线粒体功能障碍，加速NAFLD进展为 纳什。这些研究形成了这一提议的总体假设，即肝脏eNOS和eNOS衍生的一氧化氮 一氧化氮(NO)在维持正常的肝线粒体功能和质量控制中起着至关重要的作用 纳什的名字。虽然eNOS和NO对过氧化物体增殖物激活的伽马的调节作用已被证实 共激活因子α(pGC-1α)，控制线粒体的核转录因子的共同激活因子 生物发生，我们最近收集了新的初步数据，eNOS缺乏也会导致戏剧性的 降低核因子-E_2相关因子-2(NRF2/NFE2L2)和肝自噬标记物 有丝分裂，负责清除受损细胞器和线粒体的细胞过程。损失 内皮型一氧化氮合酶缺乏症的吞丝分裂伴随着过氧化氢的释放增加，抗氧化能力降低 能力和对西方饮食(高脂肪、蔗糖、胆固醇)的易感性诱发NASH。我们将利用 饮食、药理学、体内和体外分子方法(功能的得失研究) 机制研究肝细胞eNOS与有丝分裂原在发育和发育过程中的新联系 纳什的进展。具体的目的将：(1)确定肝细胞eNOS在易感性中的作用。 NASH，(2)测试靶向NRF2和BNIP3是否增加有丝分裂并拯救NASH，以及(3)测试是否 线粒体靶向抗氧化防御上调可减轻西方饮食诱导的NASH。这些 研究将为减少我们退伍军人中NASH的发生率提供洞察力。

Nonalcoholic fatty liver disease (NAFLD) comprises a spectrum of liver pathologies from simple steatosis to nonalcoholic steatohepatitis (NASH; hepatic inflammation and fibrosis) and cirrhosis. NAFLD affects greater than 30% of the general US adult population, and disturbingly, prevalence rates of NAFLD and NASH appear to be greater in the military and veteran population. NASH is directly linked to increased liver-related, cardiovascular disease and all-cause mortality and also the need for liver transplantation. Previous studies from our group and others indicate that mitochondrial dysfunction is linked to NASH development and progression. Unfortunately, mechanism(s) that regulate hepatic mitochondrial function and increased susceptibility to NASH are largely unknown. Our group has recently demonstrated that normal endothelial nitric oxide synthase (eNOS) activation is lost in an obese rat model during the transition to NASH, and that systemic NOS inhibition causes hepatic mitochondrial dysfunction and accelerates NAFLD progression to NASH. These studies form the overall hypothesis of this proposal, that hepatic eNOS and eNOS-derived nitric oxide (NO) are critical in maintaining normal hepatic mitochondrial function and quality control in the prevention of NASH. While it is well established that eNOS and NO regulate peroxisome proliferator-activated gamma co-activator alpha (PGC-1α), a co-activator of nuclear transcriptional factors that control mitochondrial biogenesis, we have recently collected novel preliminary data that eNOS deficiency also causes a dramatic reduction nuclear factor-E2-related factor-2 (NRF2/NFE2L2) and in markers of hepatic autophagy and mitophagy, the cellular processes responsible for clearance of damage organelles and mitochondria. The loss of mitophagy in eNOS deficiency occur in conjunction with increased H2O2 emission, reduced anti-oxidative capacity, and susceptibility to western diet (high fat, sucrose, cholesterol) induced NASH. We will utilize dietary, pharmacological, and in vivo and in vitro molecular approaches (gain and loss of function studies) to mechanistically examine the novel links between hepatocellular eNOS and mitophagy in the development and progression of NASH. The specific aims will: (1) determine the role of hepatocellular eNOS in susceptibility to NASH, (2) test if targeting NRF2 and BNIP3 increases mitophagy and rescues NASH, and (3) test if upregulation in mitochondrial-targeted antioxidant defense alleviates western diet induced NASH. These studies will provide insight into reducing the incidence of NASH in our Veteran population.