AICAR-Induced AMPK Activation Inhibits the Noncanonical NF-κB Pathway to Attenuate Liver Injury and Fibrosis in BDL Rats

Abstract

Background To evaluate the AMP-activated protein kinase- (AMPK-) mediated signaling and NF-κB-related inflammatory pathways that contribute to cholestatic diseases in the bile duct ligation (BDL) rat model of chronic cholestasis and verify the protective role of 5-Aminoimidazole-4-carboxamide1-β-D-ribofuranoside (AICAR) against hepatic injury and fibrosis triggered by cholestasis-related inflammation. Methods Animals were randomly divided into three groups: sham-operated group, BDL group, and BDL+ AICAR group. Cholestatic liver injury was induced by common BDL. Two weeks later, rats in BDL+AICAR group started receiving AICAR treatment. Hepatic pathology was examined by haematoxylin and eosin (H&E) and sirius red staining and hydroxyproline assay was performed in evaluating the severity of hepatic cirrhosis. Real-time PCR and Western blot were performed for RNA gene expression of RNA and protein levels, respectively. Results The BDL group showed liver injury as evidenced by histological changes and elevation in serum biochemicals, ductular reaction, fibrosis, and inflammation. The mRNA expression of canonical NF-κB inflammatory cytokines such as TNF-α, IL-1β, TGF-β, and the protein of noncanonical NF-κB, P100, and P52 was upregulated in the livers of BDL rats. The BDL rats with the administration of AICAR could induce AMPK activation inhibiting the noncanonical NF-κB pathway to attenuate liver injury and fibrosis in BDL rats. Conclusion The BDL model of hepatic cholestatic injury resulting in activation of Kupffer cells and recruitment of immune cells might initiate an inflammatory response through activation of the NF-κB pathway. The AMPK activator AICAR significantly alleviated BDL-induced inflammation in rats by mainly inhibiting the noncanonical NF-κB pathway and thus protecting against hepatic injury and fibrosis triggered by BDL.

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

“…Another important point is that TGF‐β is considered as the key promoting factor in liver fibrosis, as celastrol could up‐regulate SIRT3, whether there is a regulatory role between SIRT3 and TGF‐β? Previous study showed that SIRT3 could deacetylate and activate glycogen synthase kinase 3β (GSK‐3β) to positively regulate its activity, which phosphorylated β‐catenin and Smad to block TGF‐β1 signalling and suppress tissue fibrosis . Therefore, in the future study, the effect of celastrol on GSK‐3β, phosphorylation of β‐catenin and Smad will be investigated to clarify the regulatory role between SIRT3 and TGF‐β.…”

“…AMPK is involved in the development of many disease models including liver fibrosis and activation of AMPK inhibited NF‐κB signalling to alleviate liver inflammation and fibrosis . Liver fibrosis can also be ameliorated by AMPK phosphorylation and blockade of mTOR‐dependent cascades .…”

“…AMPK is involved in the development of many disease models including liver fibrosis and activation of AMPK inhibited NF-κB signalling to alleviate liver inflammation and fibrosis. 45 Liver fibrosis can also be ameliorated by AMPK phosphorylation and blockade of mTOR-dependent cascades. 46 Consistent with this study, the present study showed that celastrol evidently increased the expression of phosphorylation of AMPK in liver fibrosis and inhibited AMPK by Intriguingly, previous studies showed that SIRT3 could activate AMPK in some disease models.…”

“…21 AMPK has been proved involved in the pathophysiology of liver fibrosis, 22 and up-regulation of AMPK phosphorylation facilitated to the attenuation of liver fibrosis. 23 Interestingly, SIRT3 has been reported as a downstream effector of AMPK in several disease models, and activation of AMPK-SIRT3 signalling contributes to the improvement of mitochondrial function, thus alleviating the progress of diseases. 24,25 However, in liver fibrosis, whether celastrol regulate AMPK-SIRT3 signalling remains poorly understood.…”

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

“…Indeed, pharmacological activation of AMPK has been demonstrated to inhibit TGFβ-induced intracellular lipid droplets depletion and activation of LX2 cells [ 103 ]. Moreover, AMPK activation has also been shown to attenuate liver injury and fibrosis in BDL rats through non-canonical NF-κB pathway inhibition and subsequent downregulation of inflammatory cytokines such as Tnf-α , Il-β , Il-21 , and Ccl21 [ 104 ]. However, a recent study suggested that TWEAK-induced SIRT1 upregulation inhibits LX2 cells senescence in parallel with α-SMA increased expression [ 105 ].…”