Melatonin Protects Cholangiocytes from Oxidative Stress-Induced Proapoptotic and Proinflammatory Stimuli via miR-132 and miR-34

Int J Mol Sci. 2020 Dec 18;21(24):9667. doi: 10.3390/ijms21249667.

Abstract

Biosynthesis of melatonin by cholangiocytes is essential for maintaining the function of biliary epithelium. However, this cytoprotective mechanism appears to be impaired in primary biliary cholangitis (PBC). MiR-132 has emerged as a mediator of inflammation in chronic liver diseases. The effect of melatonin on oxidative stress and bile acid-induced apoptosis was also examined in cholangiocyes overexpressing miR506, as a PBC-like cellular model. In PBC patients the serum levels of melatonin were found increased in comparison to healthy controls. Whereas, in cholangiocytes within cirrhotic PBC livers the melatonin biosynthetic pathway was substantially suppressed even though the expressions of melatonin rate-limiting enzyme aralkylamine N-acetyltransferase (AANAT), and CK-19 (marker of cholangiocytes) were enhanced. In cholangiocytes exposed to mitochondrial oxidative stress melatonin decreased the expression of proapoptotic stimuli (PTEN, Bax, miR-34), which was accompanied by the inhibition of a pivotal mediator of inflammatory response Nf-κB-p65 and the activation of antiapoptotic signaling (miR-132, Bcl2). Similarly, melatonin reduced bile acid-induced proapoptotic caspase 3 and Bim levels. In summary, the insufficient hepatic expression of melatonin in PBC patients may predispose cholangiocytes to oxidative stress-related damage. Melatonin, via epigenetic modulation, was able to suppress NF-κB signaling activation and protect against biliary cells apoptotic signaling.

Keywords: apoptosis; melatonin; micro RNA; oxidative stress; primary biliary cholangitis.

MeSH terms

  • Animals
  • Apoptosis* / drug effects
  • Bile Ducts / cytology*
  • Bile Ducts / metabolism*
  • Biomarkers
  • Cells, Cultured
  • Epithelial Cells / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Immunohistochemistry
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Liver Cirrhosis, Biliary / blood
  • Liver Cirrhosis, Biliary / etiology
  • Liver Cirrhosis, Biliary / metabolism
  • Liver Cirrhosis, Biliary / pathology
  • Melatonin / metabolism*
  • Melatonin / pharmacology
  • MicroRNAs / genetics*
  • Oxidative Stress* / drug effects
  • Protective Agents / pharmacology

Substances

  • Biomarkers
  • MIRN132 microRNA, human
  • MIRN34 microRNA, human
  • MicroRNAs
  • Protective Agents
  • Melatonin