Mitochondrial mitophagy in the development and treatment of NAFLD

描述（由申请人提供）： 非酒精性脂肪性肝病（NAFLD）是肝脏胰岛素抵抗和2型糖尿病发展的重要风险因素，也与其他严重肝病状态的发展有关，包括脂肪性肝炎、肝硬化和肝癌。NAFLD被认为是VA人群中的一个重要健康问题。我们以前的研究结果表明，线粒体功能与NAFLD的发展有关。不幸的是，控制肝线粒体功能并因此改变对肝脂肪变性的易感性的机制在很大程度上仍然未知。过氧化物酶体增殖物激活的γ共激活因子α（PGC-1 β）共激活核转录因子，导致线粒体生物合成增加。PGC-1 β和线粒体功能在肥胖症中都受到抑制。相比之下，我们已经表明，在体内肝脏特异性PGC-1 β过表达（o/e）增加线粒体功能，减少肝脏脂质积累。但这些结果可能不仅仅归因于线粒体生物合成的增加。最近的数据显示，“高质量线粒体”的维持也依赖于溶酶体中低功能或受损线粒体通过称为线粒体自噬（即线粒体自噬）的过程的周转和降解。为此，我们发现PGC-1过表达也增加了自噬的标志物，这是一种以前从未被研究过的联系。该提案将测试主要假设，即PGC- 1在介导线粒体生物发生和线粒体自噬的协调共激活中发挥主要作用，这对于维持线粒体功能以及预防和治疗NAFLD是必要的。由于特定的遗传改变而具有线粒体生物发生或线粒体自噬缺陷的啮齿动物模型将用于测试相应途径的重要性。我们还将使用功能治疗的分子增益（PGC-1 β的过表达）和运动训练来调节途径，除了进行体外原代肝细胞研究以分离肝脏特异性机制并检查作为全身结果基础的急性分子变化。具体目标是：1）确定线粒体生物发生和线粒体自噬的能力受损是否由于线粒体功能降低而增加对肝脂肪变性和胰岛素抵抗的易感性，和2）。测试是否增加线粒体自噬和线粒体功能是治疗肝脂肪变性和胰岛素抵抗所必需的。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a significant risk factor for the development of hepatic insulin resistance and type 2 diabetes and is also linked to the development of other serious liver disease states including steatohepatitis, cirrhosis, and hepatic carcinoma. NAFLD is recognized as a significant health problem in the VA population. Our previous results show that mitochondrial function is linked to the development of NAFLD. Unfortunately, the mechanism(s) that govern hepatic mitochondrial function and thus alter susceptibility for hepatic steatosis remain largely unknown. Peroxisome proliferator-activated gamma co-activator alpha (PGC-1�) co-activates nuclear transcriptional factors resulting in increased mitochondrial biogenesis. Both PGC-1� and mitochondrial function are suppressed in obesity. In contrast, we have shown that in vivo liver-specific PGC-1� overexpression (o/e) increases mitochondrial function and reduces hepatic lipid accumulation. But these results may not be solely attributable to increased mitochondrial biogenesis. Recent data shows that maintenance of "high quality mitochondria" is also dependent on the turnover and degradation of low functioning or damaged mitochondria in the lysosome by a process termed mitophagy (i.e. autophagy of mitochondria). To that end we found that PGC-1� overexpression also increased markers of autophagy, a link that has never before been examined. This proposal will test the primary hypothesis that PGC- 1� plays a primary role in mediating a coordinated co-activation of mitochondrial biogenesis and mitophagy that is necessary for maintaining mitochondrial function and preventing and treating NAFLD. Rodent models that possess defects in mitochondrial biogenesis or mitophagy due to specific genetic alterations will be used to test the importance of the respective pathways. We will also use molecular gain of function therapy (overexpression of PGC-1�) and exercise training to modulate pathways, in addition to performing in-vitro primary hepatocyte studies to isolate hepatic specific mechanism(s) and examine acute molecular changes that underlie whole body results. The specific aims will: 1) Determine if impaired capacity for mitochondrial biogenesis and mitophagy increases susceptibility for hepatic steatosis and insulin resistance due to reduced mitochondrial function, and 2). Test if increased mitophagy and mitochondrial function are necessary for treatment of hepatic steatosis and insulin resistance.