Published online May 7, 2022. doi: 10.3748/wjg.v28.i17.1798
Peer-review started: October 28, 2021
First decision: December 12, 2021
Revised: December 21, 2021
Accepted: March 25, 2022
Article in press: March 25, 2022
Published online: May 7, 2022
Acute liver failure (ALF) is a life-threatening disease that can rapidly develop into multiple organ failure. The mortality rate is high. If effective treatment measures are not taken, various complications will occur, including cerebral edema, sepsis, renal failure, gastrointestinal bleeding, and respiratory failure. Hypoxia inducible factor 1α (HIF-1α) is a transcription factor that regulates oxygen homeostasis. In ALF, HIF-1α contributes to early liver cell necrosis. Sirtuin1 (Sirt1) plays a key role in health by deacetylating target proteins in many tissues, including the liver. The activation of Sirt1 will result in a powerful antioxidant defense system. However, the role of Sirt1 in ALF and the relationship between Sirt1 and HIF-1α remain unclear and require further investigation.
The results of this study might provide a basis for the application of Sirt1 in the treatment of ALF and further understanding of the mechanism of Sirt1 and HIF-1α in the process of ALF.
This study detected the changes in the expression of Sirt1 and HIF-1α in liver tissues and hepatocytes under hypoxia during the ALF process as well as the differences in the expression levels of key enzymes. In addition, this study further explored the relationship and mechanism of Sirt1 signaling pathway and HIF-1α expression.
Western blotting was used to detect the expression levels of Sirt1 and HIF-1α related proteins in mouse liver tissues, and immunofluorescence staining was used to observe the acetylation level of HIF-1α. Detection of HIF-1α and reactive oxygen species (ROS) levels and the correlation analysis between Sirt1 and HIF-1α were performed. Finally, Sirt1 was activated to observe the influence of the Sirt1 signaling pathway and HIF-1α on ALF, and changes in the expression levels of related markers were detected.
The expression of Sirt1 decreased and the level of HIF-1α acetylation increased in hypoxic mice, and the levels of carbonic anhydrase 9 and Bcl-2-adenovirus E1B interacting protein 3 increased significantly, which was regulated by HIF-1α, indicating an increase of HIF-1α activity. Under hypoxia, the down-regulation of Sirt1 activated and acetylated HIF-1α in L02 cells. The inhibition of Sirt1 significantly aggravated this effect and the massive production of ROS. The regulation of ROS was partly through peroxisome proliferator-activated receptor alpha or AMP-activated protein kinase (AMPK). The activation of Sirt1 effectively relieved ALF aggravated by hypoxia, the production of ROS, and cell apoptosis. It also induced the deacetylation of HIF-1α and inhibited the activity of HIF-1α.
The inhibition of peroxisome proliferator-activated receptor alpha and the phosphorylation of AMPK induced by hypoxia were closely related to Sirt1, and the inhibition of Sirt1/PPARα or Sirt1/AMPK signaling pathway might increase hypoxia-induced ROS production. The activation of Sirt1 reduced oxidative stress in ALF by regulating the activity and acetylation of HIF-1α.
The results of this study showed that the deacetylation and inactivation of HIF-1α induced by the activation of Sirt1 might have therapeutic benefits in reducing liver damage during ALF. This study preliminarily clarified the role of Sirt1 and HIF-1α in ALF, so as to deepen the understanding of the mechanism of ALF, and provided guidance for the selection of ALF treatment targets. The results of this study indicate that Sirt1 activator may have a certain prospective application as a therapeutic drug for ALF.