Autophagy regulates lipid metabolism through selective turnover of NCoR1
Autophagy regulates lipid metabolism through selective turnover of NCoR1
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DOI：
10.1038/s41467-019-08829-3
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发表时间：
2019-04-05
影响因子：
16.6
通讯作者：
Komatsu, Masaaki
中科院分区：
文献类型：
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作者：
Saito, Tetsuya;Kuma, Akiko;Komatsu, Masaaki
选择性自噬确保从细胞中去除特定的可溶性蛋白质、蛋白质聚集体、受损的线粒体和侵入性细菌。有缺陷的自噬与代谢紊乱直接相关。然而，选择性自噬如何调节代谢在很大程度上仍然没有表征。在这里，我们表明，选择性自噬的缺陷与脂质氧化的抑制有关。肝脏Atg 7或Atg 5缺失显著损害空腹时酮体的产生，这是由于在通过PPAR α抑制反式激活后参与β-氧化的酶的表达降低。从机制上讲，核受体辅阻遏物1（NCoR 1）与PPAR α相互作用以抑制其反式激活，与自噬体GABARAP家族蛋白结合并通过自噬降解。因此，自噬的丧失导致NCoR 1的积累，抑制PPAR α活性并导致脂质氧化受损。这些结果表明，自噬通过促进NCoR 1的降解，从而调节β-氧化和酮体的产生，促进禁食后的PPAR α活化。
Selective autophagy ensures the removal of specific soluble proteins, protein aggregates, damaged mitochondria, and invasive bacteria from cells. Defective autophagy has been directly linked to metabolic disorders. However how selective autophagy regulates metabolism remains largely uncharacterized. Here we show that a deficiency in selective autophagy is associated with suppression of lipid oxidation. Hepatic loss of Atg7 or Atg5 significantly impairs the production of ketone bodies upon fasting, due to decreased expression of enzymes involved in beta-oxidation following suppression of transactivation by PPAR alpha. Mechanistically, nuclear receptor co-repressor 1 (NCoR1), which interacts with PPAR alpha to suppress its transactivation, binds to the autophagosomal GABARAP family proteins and is degraded by autophagy. Consequently, loss of autophagy causes accumulation of NCoR1, suppressing PPAR alpha activity and resulting in impaired lipid oxidation. These results suggest that autophagy contributes to PPAR alpha activation upon fasting by promoting degradation of NCoR1 and thus regulates beta-oxidation and ketone bodies production.