Activation of TGR5 promotes mitochondrial biogenesis in human aortic endothelial cells
- Department of Internal Medicine, West China School of Medicine, Sichuan University, Chengdu 610041, Sichuan Province (China)
- Department of Pulmonary Disease, Institute of Respiratory Disease, Chengdu Second People's Hospital, Chengdu 610041, Sichuan Province (China)
Highlights: • Activation of TGR5 increases the expression of PGC-1α, NRF1 and TFAM. • Activation of TGR5 promotes mitochondrial biogenesis. • Activation of TGR5 leads to a functional gain of mitochondria. • The effect of TGR5 on mitochondrial biogenesis is mediated by CREB. Impairment of mitochondrial biogenesis has been associated with vascular pathophysiology. The G-protein–coupled receptor (TGR5) is an important mediator of bile acid signaling and glucose metabolism. However, the effects of TGR5 on mitochondrial biogenesis in endothelial cells remain elusive. In this study, we found that activation of TGR5 using its specific agonist taurolithocholic acid (TLCA) promoted the expression of PGC-1α, a master regulator of mitochondrial biogenesis in human aortic endothelial cells (HAECs). Additionally, activation of TGR5 increased the expression of PGC-1α target genes, such as NRF1 and TFAM. Indeed, we found that TLCA treatment promoted mitochondrial biogenesis by increasing mitochondrial mass, mitochondrial-to-nuclear DNA (mtDNA/nDNA), COX-Ⅰ expression, and cytochrome c oxidase activity in HAECs. Notably, our results displayed that activation of TGR5 resulted in a functional gain in mitochondria by increasing the rate of respiration and ATP production. Mechanistically, we found that TLCA treatment activated the transcriptional factor CREB by inducing the phosphorylation of CREB at Ser133. Using the PKA/CREB inhibitor H89 abolished the effects of TLCA on PGC-1α, NRF1 and TFAM expression as well as the increase in mtDNA/nDNA and ATP production. These findings suggest that activation of TGR5 promoted mitochondrial biogenesis in endothelial cells, which is mediated by the CREB/PGC-1α signaling pathway.
- OSTI ID:
- 23125146
- Journal Information:
- Biochemical and Biophysical Research Communications, Vol. 500, Issue 4; Other Information: Copyright (c) 2018 Elsevier Inc. All rights reserved.; Country of input: International Atomic Energy Agency (IAEA); ISSN 0006-291X
- Country of Publication:
- United States
- Language:
- English
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