Undamatla Ramya, Fagunloye Olayemi G, Chen Jeffrey, Edmunds Lia R, Murali Anjana, Mills Amanda, Xie Bingxian, Pangburn Martha M, Sipula Ian, Gibson Gregory, Croix Claudette St, Jurczak Michael J
University of Pittsburgh School of Medicine.
University of Pittsburgh.
Res Sq. 2023 Jan 16:rs.3.rs-2469234. doi: 10.21203/rs.3.rs-2469234/v1.
Nonalcoholic fatty liver disease (NAFLD) encompasses a spectrum of pathologies that includes steatosis, steatohepatitis (NASH) and fibrosis and is strongly associated with insulin resistance and type 2 diabetes. Changes in mitochondrial function are implicated in the pathogenesis of NAFLD, particularly in the transition from steatosis to NASH. Mitophagy is a mitochondrial quality control mechanism that allows for the selective removal of damaged mitochondria from the cell via the autophagy pathway. While past work demonstrated a negative association between liver fat content and rates of mitophagy, when changes in mitophagy occur during the pathogenesis of NAFLD and whether such changes contribute to the primary endpoints associated with the disease are currently poorly defined. We therefore undertook the studies described here to establish when alterations in mitophagy occur during the pathogenesis of NAFLD, as well as to determine the effects of genetic inhibition of mitophagy via conditional deletion of a key mitophagy regulator, PARKIN, on the development of steatosis, insulin resistance, inflammation and fibrosis. We find that loss of mitophagy occurs early in the pathogenesis of NAFLD and that loss of PARKIN hastens the onset but not severity of key NAFLD disease features. These observations suggest that loss of mitochondrial quality control in response to nutritional stress may contribute to mitochondrial dysfunction and the pathogenesis of NAFLD.
非酒精性脂肪性肝病（NAFLD）涵盖一系列病理状况，包括脂肪变性、脂肪性肝炎（NASH）和纤维化，并且与胰岛素抵抗和2型糖尿病密切相关。线粒体功能的改变与NAFLD的发病机制有关，特别是在从脂肪变性转变为NASH的过程中。线粒体自噬是一种线粒体质量控制机制，它允许通过自噬途径从细胞中选择性清除受损的线粒体。虽然过去的研究表明肝脏脂肪含量与线粒体自噬速率呈负相关，但目前对于NAFLD发病过程中线粒体自噬何时发生变化以及这种变化是否导致与该疾病相关的主要终点事件并不明确。因此，我们进行了此处所述的研究，以确定NAFLD发病过程中线粒体自噬何时发生改变，并确定通过条件性缺失关键线粒体自噬调节因子PARKIN对线粒体自噬进行基因抑制，对脂肪变性、胰岛素抵抗、炎症和纤维化发展的影响。我们发现线粒体自噬的丧失在NAFLD发病早期就已出现，并且PARKIN的缺失会加速关键NAFLD疾病特征的出现，但不会加重其严重程度。这些观察结果表明，对营养应激的反应中线粒体质量控制的丧失可能导致线粒体功能障碍和NAFLD的发病机制。
