Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis

Lixian Chen, Tianhao Zhou, Nan Wu, April O'Brien, Julie Venter, Ludovica Ceci, Konstantina Kyritsi, Paolo Onori, Eugenio Gaudio, Amelia Sybenga, Linglin Xie, Chaodong Wu, Luca Fabris, Pietro Invernizzi, David Zawieja, Suthat Liangpunsakul, Fanyin Meng, Heather Francis, Gianfranco Alpini, Qiaobing HuangShannon Glaser

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Melatonin, a neuroendocrine hormone synthesized by the pineal gland and cholangiocytes, decreases biliary hyperplasia and liver fibrosis during cholestasis-induced biliary injury via melatonin-dependent autocrine signaling through increased biliary arylalkylamine N-acetyltransferase (AANAT) expression and melatonin secretion, downregulation of miR-200b and specific circadian clock genes. Melatonin synthesis is decreased by pinealectomy (PINX) or chronic exposure to light. We evaluated the effect of PINX or prolonged light exposure on melatonin-dependent modulation of biliary damage/ductular reaction/liver fibrosis. Studies were performed in male rats with/without BDL for 1 week with 12:12 h dark/light cycles, continuous light or after 1 week of PINX. The expression of AANAT and melatonin levels in serum and cholangiocyte supernatant were increased in BDL rats, while decreased in BDL rats following PINX or continuous light exposure. BDL-induced increase in serum chemistry, ductular reaction, liver fibrosis, inflammation, angiogenesis and ROS generation were significantly enhanced by PINX or light exposure. Concomitant with enhanced liver fibrosis, we observed increased biliary senescence and enhanced clock genes and miR-200b expression in total liver and cholangiocytes. In vitro, the expression of AANAT, clock genes and miR-200b was increased in PSC human cholangiocyte cell lines (hPSCL). The proliferation and activation of HHStecs (human hepatic stellate cell lines) were increased after stimulating with BDL cholangiocyte supernatant and further enhanced when stimulated with BDL rats following PINX or continuous light exposure cholangiocyte supernatant via intracellular ROS generation. Conclusion: Melatonin plays an important role in the protection of liver against cholestasis-induced damage and ductular reaction.

Original languageEnglish (US)
Pages (from-to)1525-1539
Number of pages15
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
Volume1865
Issue number6
DOIs
StatePublished - Jun 1 2019

Keywords

  • Arylalkylamine N-acetyltransferase
  • Clock genes
  • Melatonin receptors
  • Reactive oxygen species
  • Senescence

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

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