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Melatonin inhibits hypothalamic gonadotropin-releasing hormone release and reduces biliary hyperplasia and fibrosis in cholestatic rats
- Source :
- American journal of physiology. Gastrointestinal and liver physiology. 313(5)
- Publication Year :
- 2016
-
Abstract
- Melatonin is a hormone produced by the pineal gland with increased circulating levels shown to inhibit biliary hyperplasia and fibrosis during cholestatic liver injury. Melatonin also has the capability to suppress the release of hypothalamic gonadotropin-releasing hormone (GnRH), a hormone that promotes cholangiocyte proliferation when serum levels are elevated. However, the interplay and contribution of neural melatonin and GnRH to cholangiocyte proliferation and fibrosis in bile duct-ligated (BDL) rats have not been investigated. To test this, cranial levels of melatonin were increased by implanting osmotic minipumps that performed an intracerebroventricular (ICV) infusion of melatonin or saline for 7 days starting at the time of BDL. Hypothalamic GnRH mRNA and cholangiocyte secretion of GnRH and melatonin were assessed. Cholangiocyte proliferation and fibrosis were measured. Primary human hepatic stellate cells (HSCs) were treated with cholangiocyte supernatants, GnRH, or the GnRH receptor antagonist cetrorelix acetate, and cell proliferation and fibrosis gene expression were assessed. Melatonin infusion reduced hypothalamic GnRH mRNA expression and led to decreased GnRH and increased melatonin secretion from cholangiocytes. Infusion of melatonin was found to reduce hepatic injury, cholangiocyte proliferation, and fibrosis during BDL-induced liver injury. HSCs supplemented with BDL cholangiocyte supernatant had increased proliferation, and this increase was reversed when HSCs were supplemented with supernatants from melatonin-infused rats. GnRH stimulated fibrosis gene expression in HSCs, and this was reversed by cetrorelix acetate cotreatment. Increasing bioavailability of melatonin in the brain may improve outcomes during cholestatic liver disease.NEW & NOTEWORTHY We have previously demonstrated that GnRH is expressed in cholangiocytes and promotes their proliferation during cholestasis. In addition, dark therapy, which increases melatonin, reduced cholangiocyte proliferation and fibrosis during cholestasis. This study expands these findings by investigating neural GnRH regulation by melatonin during BDL-induced cholestasis by infusing melatonin into the brain. Melatonin infusion reduced cholangiocyte proliferation and fibrosis, and these effects are due to GNRH receptor 1-dependent paracrine signaling between cholangiocytes and hepatic stellate cells.
- Subjects :
- 0301 basic medicine
Liver Cirrhosis
medicine.medical_specialty
endocrine system
Physiology
Gonadotropin-releasing hormone
Biology
Pineal Gland
Cholangiocyte
Melatonin
Gonadotropin-Releasing Hormone
03 medical and health sciences
0302 clinical medicine
Hormone Antagonists
Cholestasis
Fibrosis
Physiology (medical)
Internal medicine
medicine
Hepatic Stellate Cells
Endocrine system
Animals
Humans
Cell Proliferation
Hyperplasia
Hepatology
Biliary hyperplasia
Gastroenterology
Central Nervous System Depressants
medicine.disease
Rats
Disease Models, Animal
030104 developmental biology
Endocrinology
Hepatic stellate cell
030211 gastroenterology & hepatology
Bile Ducts
hormones, hormone substitutes, and hormone antagonists
Receptors, LHRH
medicine.drug
Research Article
Subjects
Details
- ISSN :
- 15221547
- Volume :
- 313
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- American journal of physiology. Gastrointestinal and liver physiology
- Accession number :
- edsair.doi.dedup.....6cdf19cae50378b7df243cc6d3061728