Compartmentally scavenging hepatic oxidants through AMPK/SIRT3-PGC1α axis improves mitochondrial biogenesis and glucose catabolism
| Autor: | Ben Lai, Liang Qiao, Meiling Wu, Shanlin Liu, Dongyun Shi, Chunwang Zhang, Jiankang Liu, Mengdan Xie, Yuansheng Zhen |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
medicine.medical_specialty Glucose uptake AMP-Activated Protein Kinases Biochemistry Diabetes Mellitus Experimental Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Sirtuin 3 Physiology (medical) Internal medicine Diabetes mellitus medicine Animals Organelle Biogenesis Catabolism Chemistry Type 2 Diabetes Mellitus AMPK Oxidants medicine.disease Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha Glucose 030104 developmental biology Endocrinology Diabetes Mellitus Type 2 Liver Gluconeogenesis Mitochondrial biogenesis 030217 neurology & neurosurgery |
| Zdroj: | Free Radical Biology and Medicine. 168:117-128 |
| ISSN: | 0891-5849 |
| DOI: | 10.1016/j.freeradbiomed.2021.03.029 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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