Hepatic eNOS and Mitochondrial Function in NASH

非酒精性脂肪性肝病（NAFLD）包括从单纯性脂肪变性到肝硬化的一系列肝脏病理学。 非酒精性脂肪性肝炎（NASH;肝脏炎症和纤维化）和肝硬化。NAFLD影响更大 超过30%的美国成年人，令人不安的是，NAFLD和NASH的患病率似乎 在军队和退伍军人中的比例更高。NASH与肝脏相关的， 心血管疾病和全因死亡率以及肝移植的需要。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的发展有关， 进展不幸的是，调节肝线粒体功能和增加肝细胞凋亡的机制， 对NASH易感性在很大程度上是未知的。我们的研究小组最近证明，正常内皮细胞 一氧化氮合酶（eNOS）活化在肥胖大鼠模型中在向NASH转变期间丧失， 全身性NOS抑制导致肝线粒体功能障碍并加速NAFLD进展， 纳什这些研究形成了这一提议的总体假设，即肝脏eNOS和eNOS衍生的一氧化氮合酶 一氧化氮（NO）在维持正常的肝线粒体功能和预防中的质量控制中至关重要 关于NASH虽然已经确定eNOS和NO调节过氧化物酶体增殖物激活的γ 辅激活因子α（PGC-1α），一种控制线粒体DNA的核转录因子的辅激活因子 生物起源，我们最近收集了新的初步数据，eNOS缺乏也会导致戏剧性的 减少核因子-E2相关因子-2（NRF 2/NFE 2L 2）和肝自噬标志物， 线粒体自噬，负责清除受损细胞器和线粒体的细胞过程。损失 eNOS缺陷中线粒体自噬的发生与H2 O2排放增加、抗氧化能力降低 容量和对西方饮食（高脂肪、蔗糖、胆固醇）的易感性诱导NASH。我们将利用 饮食、药理学以及体内和体外分子方法（功能获得和丧失研究）， 机械地检查肝细胞eNOS和线粒体自噬在发育中的新联系， NASH的进展具体的目标是：（1）确定肝细胞eNOS在易感性中的作用， NASH，（2）测试靶向NRF 2和BNIP 3是否增加线粒体自噬并挽救NASH，以及（3）测试靶向NRF 2和BNIP 3是否增加线粒体自噬并挽救NASH。 靶向肾脏的抗氧化防御的上调消除了西方饮食诱导的NASH。这些 这些研究将为降低退伍军人人群中NASH的发病率提供见解。

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.