Celastrol exerts anti‐inflammatory effect in liver fibrosis via activation of AMPK‐SIRT3 signalling

Abstract

Celastrol, a pentacyclic tritepene extracted from Tripterygium Wilfordi plant, showing potent liver protection effects on several liver‐related diseases. However, the anti‐inflammatory potential of celastrol in liver fibrosis and the detailed mechanisms remain uncovered. This study was to investigate the anti‐inflammatory effect of celastrol in liver fibrosis and to further reveal mechanisms of celastrol‐induced anti‐inflammatory effects with a focus on AMPK‐SIRT3 signalling. Celastrol showed potent ameliorative effects on liver fibrosis both in activated hepatic stellate cells (HSCs) and in fibrotic liver. Celastrol remarkably suppressed inflammation in vivo and inhibited the secretion of inflammatory factors in vitro. Interestingly, celastrol increased SIRT3 promoter activity and SIRT3 expression both in fibrotic liver and in activated HSCs. Furthermore, SIRT3 silencing evidently ameliorated the anti‐inflammatory potential of celastrol. Besides, we found that celastrol could increase the AMPK phosphorylation. Further investigation showed that SIRT3 siRNA decreased SIRT3 expression but had no obvious effect on phosphorylation of AMPK. In addition, inhibition of AMPK by employing compound C (an AMPK inhibitor) or AMPK1α siRNA significantly suppressed SIRT3 expression, suggesting that AMPK was an up‐stream protein of SIRT3 in liver fibrosis. We further found that depletion of AMPK significantly attenuated the inhibitory effect of celastrol on inflammation. Collectively, celastrol attenuated liver fibrosis mainly through inhibition of inflammation by activating AMPK‐SIRT3 signalling, which makes celastrol be a potential candidate compound in treating or protecting against liver fibrosis.

Epigenetics in Liver Fibrosis: Could HDACs be a Therapeutic Target?

“…An antifibrogenic role for SIRT3 has been established. SIRT3 is downregulated in primary rat HSCs and rat CCl 4 -induced fibrosis [ 108 ]. Sirt3 -KO mice develop tissue fibrosis in multiple organs including lung, kidney and liver with age [ 109 ].…”

“…SIRT3-mediated GSK-3β activation induces β-catenin phosphorylation and degradation, which is crucial to prevent HSCs transdifferentiation [ 63 , 110 ] and, in part mediates the antifibrogenic effects of the activation of AMPK signalling. Indeed, siRNA-mediated AMPK silencing suppresses SIRT3 expression [ 108 ]. It has been shown that SIRT4 is downregulated in human fibrotic liver tissues [ 113 ], although little is known about the specific role in liver fibrosis.…”

Withaferin A Exerts Preventive Effect on Liver Fibrosis through Oxidative Stress Inhibition in a Sirtuin 3-Dependent Manner

“…Besides, our previous study showed that celastrol increased SIRT3 promoter activity and SIRT3 expression both in fibrotic liver and in activated HSCs. SIRT3 siRNA attenuated the anti-inflammation effect of celastrol in liver fibrosis [ 15 ]. In line with the previous studies, this study found that WFA is a potent inducer of SIRT3 and increased the SIRT3 expression both in a PDGF-BB-induced in vitro fibrotic model and a CCl 4 -induced in vivo liver fibrosis model, and SIRT3 siRNA or SIRT3 knockout attenuated the antifibrogenic effect of WFA mainly by the inhibition of oxidative stress, thus further suggesting that SIRT3 is a promising therapeutic target for the treatment of liver-related diseases.…”

“…SIRT1 and 6 are mainly located in the nucleus. SIRT3, 4, and 5 are mainly located in mitochondria [ 15 ]. SIRT2 is the only sirtuin that is mainly located in the cytoplasm.…”

“…Growing evidence indicates that SIRT3 is beneficial in the prevention of liver-related diseases including nonalcoholic fatty liver, liver injury, and fibrosis [ 21 ]. Studies found that SIRT3 deficiency aggravated the carbon tetrachloride- (CCl 4 -) induced liver injury [ 22 ], while activation of SIRT3 contributed to the attenuation of liver fibrosis [ 15 ].…”