title: Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells.
abstract: The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved in different pathological processes, including fibrogenesis. Melatonin abrogates activation of hepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animal models of fibrosis, but it is unknown if protection associates with its inhibitory effect on the SphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl4) 5 μL g-1body wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg kg-1day-1i.p, beginning 2 weeks after the start of CCl4administration. At both 4 and 6 weeks following CCl4treatment, liver mRNA levels, protein concentration and immunohistochemical labelling for SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1, S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there was a decreased expression of S1PR2 and S1P lyase (S1PL). Melatonin attenuated liver fibrosis, as shown by a significant inhibition of the expression of α-smooth muscle actin (α-SMA), transforming growth factor (TGF)-β and collagen (Col) Ι. Furthermore, melatonin inhibited S1P production, lowered expression of SphK1, S1PR1, SP1R3, and ASMase, and increased expression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, as evidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cells also exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibition was confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signaling pathway by the indole reveals novel molecular pathways that may account for the protective effect of melatonin in liver fibrogenesis. © 2016 BioFactors, 43(2):272-282, 2017.
authors: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors: Bárbara
authors: B
authors: González-Fernández
authors: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors: Diana I
authors: DI
authors: Sánchez
authors: Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors: Irene
authors: I
authors: Crespo
authors: Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors: Beatriz
authors: B
authors: San-Miguel
authors: Department of Animal Health, University of León, León, Spain.
authors: Marcelino
authors: M
authors: Álvarez
authors: Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors: María J
authors: MJ
authors: Tuñón
authors: Institute of Biomedicine (IBIOMED), University of León, León, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), León, Spain.
authors: Javier
authors: J
authors: González-Gallego
mesh_terms: D000818:Animals; D002251:Carbon Tetrachloride / Q000633:toxicity; D002460:Cell Line; D005786:Gene Expression Regulation / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D050356:Lipid Metabolism / Q000187:drug effects; D008103:Liver Cirrhosis / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008246:Lysophospholipids / Q000378:metabolism; D008297:Male; D008550:Melatonin / Q000008:administration & dosage*; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D049349:Receptors, Lysosphingolipid / Q000096:biosynthesis; D015398:Signal Transduction / Q000187:drug effects; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase
chemical_list: D002251:Carbon Tetrachloride; D007211:Indoles; D008246:Lysophospholipids; D008550:Melatonin; D017853:Phosphotransferases (Alcohol Group Acceptor); D049349:Receptors, Lysosphingolipid; D013110:Sphingosine; D000081025:Sphingosine-1-Phosphate Receptors; D000099157:Sphingosine Kinase; C477362:S1PR1 protein, human; C060506:sphingosine 1-phosphate; C030374:indole
keywords: hepatic stellate cells; liver fibrosis; melatonin; sphingolipids