SirT1通过去乙酰化MST1调控mitophagy活性在尼克酰胺核糖保护酒精性肝病中的作用及机制

我国酒精性肝病（ALD）患病率日益增加，但发病机制不明且无特效药。我们前期发现，尼克酰胺核糖（NR）补充可减轻ALD。酒精导致细胞总体自噬水平下降，但线粒体自噬（mitophagy）被诱导，自噬流可能被阻断；下调mitophagy受体FUNDC1，上调mitophagy的抑制剂MST1，而NR提高自噬，上调FUNDC1，下调MST1，改善线粒体结构和功能，提示NR可能激活mitophagy清除受损的线粒体，但具体机制尚不清楚。我们设想补充NR激活SirT1，抑制MST1活性，激活FUNDC1介导mitophagy，减轻ALD？本研究拟通过构建SirT1, MST1, FUNDC1敲减或过表达小鼠和细胞模型，通过多种分子生物学手段证实NR可通过抑制MST1激活mitophagy减轻ALD，以完善NR补充减轻ALD的机制，为人群应用膳食补充剂NR防治ALD提供理论基础。

Prevalence of ALD in Chinese adults have been sustainably increasing, of which pathogenesis is unclear and specific therapeutic drugs lack. We previously reported that NR supplementation effectively alleviated alcohol-induced liver injuries in C57BL/6J mice. Alcohol intakes decreased the whole cell autophagy, however, mitophagy was induced and autophagy flux may be blocked by alcohol. Alcohol decreased FUNDC1, a mitophagy receptor, and increased MST1, a major inhibitor controlling mitophagy activation. NR supplementation improved autophagy, increased FUNDC1 and decreased MST1, thus maintaining normal structure and function of mitochondria, suggesting that NR might activate mitophagy to eliminate the damaged mitochondria. However, the mechanism is not entirely clear. We assumed that NR supplementation inhibited MST1 via SIRT1 activation, activated FUDC1 mediating mitophagy, and cleared damaged mitochondria, thus alleviating ALD? We intend to establish the knockdown or overexpression models of SIRT1, MST1 and FMDC1, to confirm that NR can alleviate ALD by MST1 inhibition and mitophagy activation via a variety of molecular biological methods both in vivo and in vitro. We expected to provide new theoretical basis for further application of NR supplement to prevent ALD.