2. Academic Validation
  3. Sirt6 opposes glycochenodeoxycholate-induced apoptosis of biliary epithelial cells through the AMPK/PGC-1α pathway

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

  • Cell Biosci. 2020 Mar 20;10:43. doi: 10.1186/s13578-020-00402-6.
Jiye Li  # 1 2 3 4,  Dongsheng Yu  # 2 3 5,  Sanyang Chen 1 2 3,  Yifan Liu 1 2 3,  Jihua Shi 1 2 3,  Jiakai Zhang 1 2 3,  Peihao Wen 1 2 3,  Zhihui Wang 1 2 3,  Jie Li 1 2 3,  Wenzhi Guo 1 2 3,  Shuijun Zhang 1 2 3
Affiliations

Affiliations

  • 1 1Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China.
  • 2 Henan Key Laboratory of Digestive Organ Transplantation, Zhengzhou, 450052 Henan China.
  • 3 Zhengzhou Key Laboratory of Organ Transplantation Technology & Application Engineering, Zhengzhou, 450052 Henan China.
  • 4 4Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450052 Henan China.
  • 5 5Department of Traditional Chinese Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China.
  • # Contributed equally.
PMID: 32206298 DOI: 10.1186/s13578-020-00402-6
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.

Keywords

AMPK; Cholestasis; HiBEC; PGC-1α; Sirt6.

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