Melatonin receptor 1A, but not 1B, knockout decreases biliary damage and liver fibrosis during cholestatic liver injury.

Autor: Wu N; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Carpino G; Department of MovementHuman and Health SciencesDivision of Health SciencesUniversity of Rome 'Foro Italico,'RomeItaly., Ceci L; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Baiocchi L; Hepatology UnitUniversity of Tor VergataRomeItaly., Francis H; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA.; Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA., Kennedy L; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA.; Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA., Zhou T; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Chen L; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Sato K; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Kyritsi K; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Meadows V; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA., Ekser B; Division of Transplant SurgeryDepartment of SurgeryIndiana UniversityIndianapolisIndianaUSA., Franchitto A; Department of AnatomicalHistologicalForensic Medicine and Orthopedic SciencesSapienza University of RomeRomeItaly., Mancinelli R; Department of AnatomicalHistologicalForensic Medicine and Orthopedic SciencesSapienza University of RomeRomeItaly., Onori P; Department of AnatomicalHistologicalForensic Medicine and Orthopedic SciencesSapienza University of RomeRomeItaly., Gaudio E; Department of AnatomicalHistologicalForensic Medicine and Orthopedic SciencesSapienza University of RomeRomeItaly., Glaser S; Department of Medical PhysiologyTexas A&M University College of MedicineBryanTexasUSA., Alpini G; Hepatology and Gastroenterology, MedicineIndiana UniversityIndianapolisIndianaUSA.; Richard L. Roudebush VA Medical CenterIndianapolisIndianaUSA.
Jazyk: angličtina
Zdroj: Hepatology (Baltimore, Md.) [Hepatology] 2022 Apr; Vol. 75 (4), pp. 797-813. Date of Electronic Publication: 2021 Nov 24.
DOI: 10.1002/hep.32233
Abstrakt: Background and Aims: Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors 1A (MT1) and 1B (MT2). MT1 and MT2 can form heterodimers and homodimers, but MT1 and MT2 can heterodimerize with the orphan receptor G protein-coupled receptor 50 (GPR50). MT1/GPR50 dimerization blocks melatonin binding, but MT2/GPR50 dimerization does not affect melatonin binding. GPR50 can dimerize with TGFβ receptor type I (TGFβRI) to activate this receptor. We aimed to determine the differential roles of MT1 and MT2 during cholestasis.
Approach and Results: Wild-type (WT), MT1 knockout (KO), MT2KO, and MT1/MT2 double KO (DKO) mice underwent sham or bile duct ligation (BDL); these mice were also treated with melatonin. BDL WT and multidrug resistance 2 KO (Mdr2 -/- ) mice received mismatch, MT1, or MT2 Vivo-Morpholino. Biliary expression of MT1 and GPR50 increases in cholestatic rodents and human primary sclerosing cholangitis (PSC) samples. Loss of MT1 in BDL and Mdr2 -/- mice ameliorated biliary and liver damage, whereas these parameters were enhanced following loss of MT2 and in DKO mice. Interestingly, melatonin treatment alleviated BDL-induced biliary and liver injury in BDL WT and BDL MT2KO mice but not in BDL MT1KO or BDL DKO mice, demonstrating melatonin's interaction with MT1. Loss of MT2 or DKO mice exhibited enhanced GPR50/TGFβR1 signaling, which was reduced by loss of MT1.
Conclusions: Melatonin ameliorates liver phenotypes through MT1, whereas down-regulation of MT2 promotes liver damage through GPR50/TGFβR1 activation. Blocking GPR50/TGFβR1 binding through modulation of melatonin signaling may be a therapeutic approach for PSC.
(© 2021 American Association for the Study of Liver Diseases. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)
Databáze: MEDLINE
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