Pinealectomy or light exposure exacerbates biliary damage and liver fibrosis in cholestatic rats through decreased melatonin synthesis.
Animals
Arylalkylamine N-Acetyltransferase
/ genetics
Bile Ducts, Intrahepatic
/ metabolism
CLOCK Proteins
/ genetics
Cell Line
Cell Proliferation
/ radiation effects
Cholestasis
/ genetics
Epithelial Cells
/ metabolism
Gene Expression Regulation
Hepatic Stellate Cells
/ metabolism
Humans
Kupffer Cells
/ metabolism
Light
Liver
/ metabolism
Liver Cirrhosis
/ genetics
Male
Melatonin
/ biosynthesis
MicroRNAs
/ genetics
Pineal Gland
/ metabolism
Pinealectomy
/ methods
Primary Cell Culture
Rats
Rats, Inbred F344
Signal Transduction
Arylalkylamine N-acetyltransferase
Clock genes
Melatonin receptors
Reactive oxygen species
Senescence
Journal
Biochimica et biophysica acta. Molecular basis of disease
ISSN: 1879-260X
Titre abrégé: Biochim Biophys Acta Mol Basis Dis
Pays: Netherlands
ID NLM: 101731730
Informations de publication
Date de publication:
01 06 2019
01 06 2019
Historique:
received:
26
01
2019
revised:
11
03
2019
accepted:
14
03
2019
pubmed:
21
3
2019
medline:
6
2
2020
entrez:
21
3
2019
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 30890428
pii: S0925-4439(19)30076-6
doi: 10.1016/j.bbadis.2019.03.002
pmc: PMC6993622
mid: NIHMS1067232
pii:
doi:
Substances chimiques
MIRN200 microRNA, rat
0
MicroRNAs
0
CLOCK Proteins
EC 2.3.1.48
Aanat protein, rat
EC 2.3.1.87
Arylalkylamine N-Acetyltransferase
EC 2.3.1.87
Melatonin
JL5DK93RCL
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1525-1539Subventions
Organisme : NIDDK NIH HHS
ID : R01 DK108959
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK062975
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107310
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK082435
Pays : United States
Organisme : BLRD VA
ID : I01 BX000574
Pays : United States
Organisme : BLRD VA
ID : I01 BX003031
Pays : United States
Organisme : BLRD VA
ID : IK6 BX004601
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK110035
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK054811
Pays : United States
Organisme : BLRD VA
ID : I01 BX001724
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK076898
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier B.V. All rights reserved.
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