title: Melatonin suppresses activation of hepatic stellate cells through RORα-mediated inhibition of 5-lipoxygenase.
abstract: Liver fibrosis is scar tissue resulting from an uncontrolled wound-healing process in response to chronic liver injury. Liver damage generates an inflammatory reaction that activates hepatic stellate cells (HSC) that transdifferentiate from quiescent cells that control retinol metabolism to proliferative and migratory myofibroblasts that produce excessive amounts of extracellular matrix proteins, in particular collagen 1a1 (COL1A1). Although liver fibrosis is reversible, no effective drug therapy is available to prevent or reverse HSC activation. Melatonin has potent hepatoprotective properties in a variety of acute and chronic liver injury models and suppresses liver fibrosis. However, it remains unclear whether melatonin acts indirectly or directly on HSC to prevent liver fibrosis. Here, we studied the effect of melatonin on culture-activated rat HSC. Melatonin dose-dependently suppressed the expression of HSC activation markers Col1a1 and alpha-smooth muscle actin (αSMA, Acta2), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor-related orphan receptor-alpha (RORα/Nr1f1) was expressed in quiescent and activated HSC, while the membranous melatonin receptors (Mtrn1a and Mtrn1b) were not. The synthetic RORα agonist SR1078 more potently suppressed Col1a1 and αSma expression, HSC proliferation, and lipid droplet loss, while the RORα antagonist SR1001 blocked the antifibrotic features of melatonin. Melatonin and SR1078 inhibited the expression of Alox5, encoding 5-lipoxygenase (5-LO). The pharmacological 5-LO inhibitor AA861 reduced Acta2 and Col1a1 expression in activated HSC. We conclude that melatonin directly suppresses HSC activation via RORα-mediated inhibition of Alox5 expression, which provides novel drug targets to treat liver fibrosis.
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Shiva
authors: S
authors: Shajari
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Institute of Biomedicine (IBIOMED), University of León, León, Spain.
authors: Almudena
authors: A
authors: Laliena
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.|Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Janette
authors: J
authors: Heegsma
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 Jesús
authors: MJ
authors: Tuñón
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Han
authors: H
authors: Moshage
authors: Department of Gastroenterology and Hepatology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors: Klaas Nico
authors: KN
authors: Faber
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism*; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism; D008550:Melatonin / Q000494:pharmacology* / Q000627:therapeutic use; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism*; D051381:Rats
chemical_list: D000975:Antioxidants; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D001094:Arachidonate 5-Lipoxygenase; D008550:Melatonin
keywords: 5-lipoxygenase; hepatic stellate cell; hepatic stellate cell activation; liver fibrosis; melatonin; proliferation; retinoic acid receptor-related orphan receptor α