Melatonin or Dark Therapy Reduce Biliary Damage, Inflammation and Liver Fibrosis in a Murine Model of Early Stage Primary Biliary Cholangitis

Abstract

BackgroundPrimary biliary cholangitis (PBC) is characterized by increased biliary damage, inflammation and liver fibrosis. Early stage PBC is marked by biliary proliferation, whereas late stage PBC shows ductopenia. We have shown that dominant‐negative transforming growth factor b receptor II (dnTGFβRII) mice at 12 wk of age mimic early stage PBC. We have found that melatonin therapy or prolonged exposure to complete darkness reduces biliary hyperplasia and liver fibrosis in models of cholestasis. However, the impact of melatonin or dark therapy on PBC‐related injury is unknown. The aim of our study was to evaluate the effects of melatonin or dark therapy in a mouse model of early stage PBC.MethodsWe used background‐matched, male wild‐type (WT) and dnTGFβRII at 12 wk of age that were given drinking water containing melatonin (0.03%) or placed in complete darkness for 1 wk along with the related controls. Liver damage was evaluated by H&E. Intrahepatic bile duct mass (IBDM) was measured by CK‐19 staining. Biliary senescence was evaluated by staining for p16 and p21, and SA‐β‐galactosidase activity. Biliary and liver inflammation were determined by IL‐6 and F4/80 (Kupffer cell marker) staining. Liver fibrosis was determined by Sirius Red staining and immunofluorescence for collagen type‐1a. Hepatic stellate cell (HSC) activation was shown by SYP‐9 and α‐SMA staining. Human control and early stage PBC serum samples were obtained, and serum melatonin levels were measured by EIA.ResultsdnTGFβRII at 12 wk of age (early stage PBC mouse model) treated with melatonin or complete darkness had decreased (i) IBDM, (ii) biliary senescence, (iii) liver fibrosis, (iv) biliary and liver inflammation, and (v) HSC activation/liver fibrosis. Human early stage PBC samples had decreased serum melatonin levels.ConclusionInhibition of melatonin signaling perpetuates biliary damage associated with PBC. Restoration of melatonin‐dependent signaling via melatonin treatment or dark therapy may be therapeutic for patients with early stage PBC.Support or Funding InformationNIH NIDDK R01, VA MeritThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.