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
The occurrence and development of acute liver failure (ALF) is closely related to a series of inflammatory reactions, such as the production of reactive oxygen species (ROS). Hypoxia inducible factor 1α (HIF-1α) is a key factor that regulates oxygen homeostasis and redox, and the stability of HIF-1α is related to the ROS level regulated by Sirtuin (Sirt) family. The activation of Sirt1 will lead to a powerful antioxidant defense system and therapeutic effects in liver disease. However, little is known about the relationship between HIF-1α and Sirt1 in the process of ALF and the molecular mechanism.
To investigate whether HIF-1α may be a target of Sirt1 deacetylation and what the effects on ALF are.
Mice were administrated lipopolysaccharide (LPS)/D-gal and exposed to hypoxic conditions as animal model, and resveratrol was used as an activator of Sirt1. The cellular model was established with L02 cells stimulated by LPS. N-acetyl-L-cysteine was used to remove ROS, and the expression of Sirt1 was inhibited by nicotinamide. Western blotting was used to detect Sirt1 and HIF-1α activity and related protein expression. The possible signaling pathways involved were analyzed by immunofluorescent staining, co-immunoprecipitation, dihydroethidium staining, and Western blotting.
Compared with mice stimulated with LPS alone, the expression of Sirt1 decreased, 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. Resveratrol, a Sirt1 activator, 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.
Sirt1 may have a protective effect on ALF by inducing HIF-1α deacetylation to reduce ROS.
Core Tip: Hypoxia inducible factor 1α (HIF-1α) is a transcription factor that regulates oxygen homeostasis. Under hypoxic conditions, HIF-1α translocates to the nucleus and binds to β-subunits, resulting in transcription of target genes. In acute liver failure, HIF-1α contributes to early liver cell necrosis. The activation of Sirtuin1 (Sirt1) will result in a powerful antioxidant defense system. This study examined the influence of Sirt1-mediated pathways on HIF-1α expression in vivo and in vitro, explored the relationship between Sirt1 and HIF-1α, and further explored its potential mechanism.