Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism
Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism
复制标题
通过 AMPK/SIRT3-PGC1α 轴分室清除肝脏氧化剂可改善线粒体生物发生和葡萄糖分解代谢
DOI：
10.1016/j.freeradbiomed.2021.03.029
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发表时间：
2021
影响因子：
7.4
通讯作者：
Shi D
中科院分区：
文献类型：
--
作者：
Wu M;Zhang C;Xie M;Zhen Y;Lai B;Liu J;Qiao L;Liu S;Shi D
早期治疗可以预防糖尿病的发生；然而，到目前为止，几乎没有药物治疗策略。肝脏是主要的代谢器官，1型和2型糖尿病患者肝脏葡萄糖代谢失衡。然而，专门针对肝脏预防糖尿病的潜力尚未得到充分开发。在本研究中，我们发现，利用线粒体靶向的ROS清除剂纳米MitoPBN隔室抑制肝脏氧化剂可以有效预防糖尿病。我们的结果表明，纳米MitoPBN逆转了糖尿病小鼠肝脏中前列腺素C-1α的下调和糖异生的增强。PGC-1α通过AMPK和SIRT3介导的机制，促进线粒体生物发生，增加线粒体数量，提高有氧氧化速率，通过增加肝脏对葡萄糖的摄取和分解代谢，导致血液中葡萄糖水平的降低。此外，PGC-1α活性的增加并未促进糖异生的激活。我们的研究表明，在糖尿病早期，PGC-1α通过调节肝脏线粒体的氧化还原平衡，选择性地抑制肝脏的糖异生，促进肝脏线粒体功能，从而加速肝脏葡萄糖的分解代谢，降低血糖。因此，仅通过三周的干预就可以使葡萄糖耐量正常化。我们的结果表明纳米MitoPBN可以在短时间内有效地预防糖尿病，突出了糖尿病早期干预的有效性和重要性，并提示了肝线粒体靶向氧化剂纳米抑制剂在糖尿病预防和早期治疗中的潜在优势。
Early treatment can prevent the occurrence of diabetes; however, there are few pharmacological treatment strategies to date. The liver is a major metabolic organ, and hepatic glucose homeostasis is dysregulated in type 1 and type 2 diabetes mellitus. However, the potential of specifically targeting the liver to prevent diabetes has not been fully exploited. In this study, we found that compartmentally inhibiting hepatic oxidants by nano-MitoPBN, a liver mitochondrial-targeting ROS scavenger, could effectively prevent diabetes. Our results demonstrated that nano-MitoPBN reversed the downregulation of PGC-1α and the enhanced gluconeogenesis in the livers of diabetic mice. PGC-1α, through an AMPK- and SIRT3-mediated mechanism, promoted mitochondrial biogenesis, increased the number of mitochondria, and enhanced the rate of aerobic oxidation, leading to decreased glucose levels in the blood by increasing glucose uptake and catabolism in the liver. Moreover, the increase in PGC-1α activity did not promote the activation of gluconeogenesis. Our study demonstrated that by regulating the redox balance of liver mitochondria in the early stage of diabetes, PGC-1α could selectively inhibit gluconeogenesis in the liver and promote hepatic mitochondrial function, which accelerated the catabolism of hepatic glucose and reduced blood glucose. Thus, glucose tolerance can be normalized through only three weeks of intervention. Our results showed that nano-MitoPBN could effectively prevent diabetes in a short period of time, highlighting the effectiveness and importance of early intervention for diabetes and suggesting the potential advantages of hepatic mitochondrial targeting oxidants nano-inhibitors in the prevention and early treatment of diabetes.