Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

Abstract

Background: Induction of biliary epithelial cell apoptosis by toxic bile acids is involved in the development of cholestatic disease, but the underlying molecular mechanism is not clear. The purpose of this study was to investigate the molecular mechanisms involved in Sirt6 protection against the apoptosis of human intrahepatic biliary epithelial cells (HiBEC) induced by the bile acid glycochenodeoxycholate (GCDC). Results: Sirt6 was either overexpressed or knocked down in HiBEC, with or without GCDC pretreatment. The CCK-8 assay was used to assess cell viability and, Hoechst 33258 staining was used to determine apoptotic rate. Mitochondrial DNA (mtDNA) copy number, malondialdehyde (MDA) and reactive oxygen species (ROS) production were detected to evaluate the severity of the mitochondrial dysfunction and oxidative stress. The mRNA and protein levels of PGC-1α, Nrf1, and Nrf2 were analyzed using RT-qPCR and western blot assay. The results showed that Sirt6 opposed GCDC-induced apoptosis in HiBEC via up-regulating PGC-1α expression and stabilizing mtDNA. We used agonists and inhibitors of AMPK to demonstrate that Sirt6 increased PGC-1α expression through the AMPK pathway whereas GCDC had the opposite effect. Finally, western blot, luciferase assay, and co-immunoprecipitation were used to describe a direct interaction and acetylation modification of PGC-1α by Sirt6. Conclusion: Our data illuminated that Sirt6 ameliorated GCDC-induced HiBEC apoptosis by upregulating PGC-1α expression through the AMPK pathway and its deacetylation effect.

Melatonin attenuates diabetic cardiomyopathy and reduces myocardial vulnerability to ischemia‐reperfusion injury by improving mitochondrial quality control: Role of SIRT6

“…65 Moreover, recent studies showed that SIRT6-mediated AMPK activation reduced mitochondrial dysfunction in either high-glucose-cultured podocytes or glycochenodeoxycholate-pretreated biliary epithelial cells. 66,67 Our results showed that SIRT6 and AMPK-PGC-1α-AKT signaling were further inhibited by diabetic MI/R injury. Long-term melatonin administration reduced the vulnerability of diabetic heart toward MI/R injury by preserving mitochondrial quality control and activating SIRT6 and AMPK-PGC-1α-AKT signaling.…”

Oridonin ameliorates acetaminophen‐induced acute liver injury through ATF4/PGC‐1α pathway

“…PGC‐1α is upstream of NRF1/NRF2, and TFAM regulates mtDNA replication and cellular oxidative metabolism (J. Li, Yu et al, 2020). Our results found that APAP treatment increased ROS production and decreased PGC‐1α levels.…”

Activation of Silent Information Regulator 6 Signaling Attenuates Myocardial Fibrosis by Reducing TGFβ1-Smad2/3 Signaling in a Type 2 Diabetic Animal Model

“…More importantly, Wang et al [14] revealed that upregulation of cardiac SIRT6 exerted a positive effect on myocardial AMPK signaling and eventually protected against myocardial ischemia/reperfusion (MI/R) injury. Recent evidence also suggests that the SIRT6-AMPK pathway inhibits mitochondrial abnormalities in podocytes or biliary epithelial cells [15,16] . In view of these critical findings, we hypothesized that in diabetic conditions, SIRT6 upregulation might retards diabetes-induced ventricular remodeling through the AMPK pathway.…”

“…Recent evidence also suggests that the SIRT6-AMPK pathway inhibits mitochondrial abnormalities in podocytes or biliary epithelial cells. [15,16] In view of these critical findings, we hypothesized that in diabetic conditions, SIRT6 upregulation might retards diabetes-induced ventricular remodeling through the AMPK pathway.…”