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 journalArticle

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)
JournalBiochimica et Biophysica Acta - Molecular Basis of Disease
DOIs
StatePublished - Jan 1 2019

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Melatonin
Liver Cirrhosis
Light
Arylalkylamine N-Acetyltransferase
Cholestasis
Autocrine Communication
Genes
Cell Line
Hepatic Stellate Cells
Circadian Clocks
Pineal Gland
Liver
Photoperiod
Serum
Hyperplasia
Down-Regulation
Hormones
Inflammation
Wounds and Injuries

Keywords

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

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology

Cite this

Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis. / Chen, Lixian; Zhou, Tianhao; Wu, Nan; O'Brien, April; Venter, Julie; Ceci, Ludovica; Kyritsi, Konstantina; Onori, Paolo; Gaudio, Eugenio; Sybenga, Amelia; Xie, Linglin; Wu, Chaodong; Fabris, Luca; Invernizzi, Pietro; Zawieja, David; Liangpunsakul, Suthat; Meng, Fanyin; Francis, Heather; Alpini, Gianfranco; Huang, Qiaobing; Glaser, Shannon.

In: Biochimica et Biophysica Acta - Molecular Basis of Disease, 01.01.2019.

Research output: Contribution to journalArticle

Chen, L, Zhou, T, Wu, N, O'Brien, A, Venter, J, Ceci, L, Kyritsi, K, Onori, P, Gaudio, E, Sybenga, A, Xie, L, Wu, C, Fabris, L, Invernizzi, P, Zawieja, D, Liangpunsakul, S, Meng, F, Francis, H, Alpini, G, Huang, Q & Glaser, S 2019, 'Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis', Biochimica et Biophysica Acta - Molecular Basis of Disease. https://doi.org/10.1016/j.bbadis.2019.03.002
Chen, Lixian ; Zhou, Tianhao ; Wu, Nan ; O'Brien, April ; Venter, Julie ; Ceci, Ludovica ; Kyritsi, Konstantina ; Onori, Paolo ; Gaudio, Eugenio ; Sybenga, Amelia ; Xie, Linglin ; Wu, Chaodong ; Fabris, Luca ; Invernizzi, Pietro ; Zawieja, David ; Liangpunsakul, Suthat ; Meng, Fanyin ; Francis, Heather ; Alpini, Gianfranco ; Huang, Qiaobing ; Glaser, Shannon. / Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis. In: Biochimica et Biophysica Acta - Molecular Basis of Disease. 2019.
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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.",
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AU - Chen, Lixian

AU - Zhou, Tianhao

AU - Wu, Nan

AU - O'Brien, April

AU - Venter, Julie

AU - Ceci, Ludovica

AU - Kyritsi, Konstantina

AU - Onori, Paolo

AU - Gaudio, Eugenio

AU - Sybenga, Amelia

AU - Xie, Linglin

AU - Wu, Chaodong

AU - Fabris, Luca

AU - Invernizzi, Pietro

AU - Zawieja, David

AU - Liangpunsakul, Suthat

AU - Meng, Fanyin

AU - Francis, Heather

AU - Alpini, Gianfranco

AU - Huang, Qiaobing

AU - Glaser, Shannon

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

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KW - Reactive oxygen species

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