MT1 but not MT2 melatonin receptor knockout decreases biliary damage and liver fibrosis during cholestatic liver injury

Background & aims: Melatonin reduces biliary damage and liver fibrosis in cholestatic models by interaction with melatonin receptors, MT1 and MT2. MT1 and MT2 can form hetero- and homo-dimers, 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 transforming growth factorβ receptor type I (TGFβRI) to activate this receptor. We aimed to determine the differential roles of MT1 and MT2 during cholestasis. Approach & 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 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 BDL MT1KO or BDL DKO mice, demonstrating melatonin 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 via MT1, whereas downregulation of MT2 promotes liver damage via GPR50/TGFβR1 activation. Blocking GPR50/TGFβR1 binding via modulation of melatonin signaling may be a therapeutic approach for PSC.