MITOCHONDRIAL ABNORMALITIES IN NAFL ? NONALCOHOLIC FATTY LIVER

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。线粒体功能障碍似乎在脂肪肝中起关键作用。由于肥胖和糖尿病的日益流行，这种形式的肝脏疾病（通常被称为NASH或NAFL）正在达到流行病的程度。在功能上，脂肪肝在体外生化试验和体内MR Spec试验中ATP减少，ETC复合物表达减少，解偶联蛋白表达增加，凋亡增加。从形态上看，透射电镜下的线粒体通常肿胀，含有晶体包裹体，这些包裹体似乎与嵴连续，表明构象发生了变化。它们与植物病变体的相似性进一步表明它们在脂质双分子层的异常形成中有共同的起源。这些形式的存在与脂质过氧化指数相关，但与光显微损伤程度无关，这表明它们可能是一种适应氧化应激的机制。三维EM成像可能为这些结构的起源提供额外的线索，这可能有助于更好地了解NAFL的发病机制和最佳治疗方法。这也可能与相关的神经退行性疾病和肝细胞癌有关，这些疾病通常包含脂肪变性区域。我打算利用这些数据向NIH和其他来源申请额外的资金。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Mitochondrial dysfunction appears to play a key role in fatty liver. This form of liver disease (commonly referred to as NASH or NAFL) is reaching epidemic proportions due to the increasing prevalence of obesity and diabetes. Functionally, the fatty liver has diminished ATP in vitro by biochemical tests and in vivo by MR Spec, decreased expression of ETC complexes, increased expression of uncoupling protein, and apoptosis is increased in these livers. Morphologically, by TEM the mitochondria are commonly swollen and contain crystalline inclusions which appear to be in continuity with the cristae suggesting a conformational change. Their resemblance to plant etioplasts further suggest a common origin in abnormal formation of a lipid bilayer. The presence of these forms correlates to indices of lipid peroxidation but not to the degree of light microscopic injury suggesting that these may serve as an adaptive mechanism to oxidative stress. Three-dimensional EM imaging may provide additional clues to the origin of these structures and this may provide better understanding of the pathogenesis of NAFL and its optimal therapy. There may also be implications for associated neurodegenerative diseases and hepatocellular cancer which commonly contains areas of steatosis. It is my intention to use this data to apply for NIH and other sources for additional funding.