Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis.
Reduced mitophagy is an early feature of NAFLD and liver-specific PARKIN knockout hastens the onset of steatosis, inflammation and fibrosis.
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DOI：
10.1038/s41598-023-34710-x
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发表时间：
2023-05-10
影响因子：
4.6
通讯作者：
Jurczak, M. J.
中科院分区：
文献类型：
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作者：
Undamatla, R.;Fagunloye, O. G.;Chen, J.;Edmunds, L. R.;Murali, A.;Mills, A.;Xie, B.;Pangburn, M. M.;Sipula, I.;Gibson, G.;St. Croix, C.;Jurczak, M. J.
非酒精性脂肪性肝病（NAFLD）包括一系列病理，包括脂肪变性、脂肪性肝炎（NASH）和纤维化，并与胰岛素抵抗和2型糖尿病密切相关。线粒体功能的变化与NAFLD的发病机制有关，特别是在从脂肪变性向NASH的转变中。线粒体自噬是一种线粒体质量控制机制，允许通过自噬途径从细胞中选择性去除受损的线粒体。虽然过去的工作表明肝脏脂肪含量和线粒体自噬率之间存在负相关性，但在NAFLD发病过程中线粒体自噬发生变化时，以及这些变化是否有助于与疾病相关的主要终点，目前尚不清楚。因此，我们进行了本文所述的研究，以确定在NAFLD发病过程中何时发生线粒体自噬的改变，以及确定通过条件性缺失关键线粒体自噬调节因子PARKIN对线粒体自噬的遗传抑制对脂肪变性、胰岛素抵抗、炎症和纤维化发展的影响。我们发现，线粒体自噬的丧失发生在NAFLD发病的早期，PARKIN的丧失加速了关键NAFLD疾病特征的发作。这些观察结果表明，响应于营养应激的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。
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 accelerates the onset 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.
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影响因子：
16
作者：
Hirschey MD;Shimazu T;Jing E;Grueter CA;Collins AM;Aouizerat B;Stančáková A;Goetzman E;Lam MM;Schwer B;Stevens RD;Muehlbauer MJ;Kakar S;Bass NM;Kuusisto J;Laakso M;Alt FW;Newgard CB;Farese RV Jr;Kahn CR;Verdin E
通讯作者：
Verdin E
影响因子：
56.9
作者：
Choudhary, Chunaram;Kumar, Chanchal;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
7.7
作者：
Kazlauskaite A;Martínez-Torres RJ;Wilkie S;Kumar A;Peltier J;Gonzalez A;Johnson C;Zhang J;Hope AG;Peggie M;Trost M;van Aalten DM;Alessi DR;Prescott AR;Knebel A;Walden H;Muqit MM
通讯作者：
Muqit MM
影响因子：
13.6
作者：
Berardi, Damian E.;Bock-Hughes, Althea;Terry, Alexander R.;Drake, Lauren E.;Bozek, Grazyna;Macleod, Kay F.
通讯作者：
Macleod, Kay F.
影响因子：
82.9
作者：
通讯作者：
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