Melatonin suppresses activation of hepatic stellate cells through RORα‐mediated inhibition of 5‐lipoxygenase. Issue 3 (15th September 2015)

• Record Type: Journal Article
• Authors: Shajari, Shiva; Laliena, Almudena; Heegsma, Janette; Tuñón, María Jesús; Moshage, Han; Faber, Klaas Nico
• Is Part Of: Journal of pineal research. Volume 59:Issue 3(2015)
• Page Start: 391
• Page End: 401
• Publication Date: 2015-09-15
• Subjects: Pineal gland -- Periodicals; Pineal Gland -- Periodicals; Épiphyse (Glande); Périodique électronique (Descripteur de forme); Ressource Internet (Descripteur de forme); 612.492
• DOI: 10.1111/jpi.12271
• Languages: English
• ISSNs: 0742-3098

Abstract

<abstract abstract-type="main" id="jpi12271-abs-0001"> <title>Abstract</title> <p>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 <italic>Col1a1</italic> and alpha‐smooth muscle actin (<italic>α</italic>SMA, <italic> Acta2</italic>), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor‐related orphan receptor‐alpha (ROR<italic>α</italic>/<italic>Nr1f1</italic>) was expressed in quiescent and activated HSC, while the membranous melatonin receptors (<italic>Mtrn1a</italic> and <italic>Mtrn1b</italic>) were not. The synthetic ROR<italic>α</italic> agonist SR1078 more potently suppressed <italic>Col1a1</italic> and <italic>αSma</italic> expression, HSC proliferation, and lipid droplet loss, while the ROR<italic>α</italic> antagonist SR1001 blocked the antifibrotic features of melatonin. Melatonin and SR1078 inhibited the expression of <italic>Alox5</italic>, encoding 5‐lipoxygenase (5‐LO). The pharmacological 5‐LO inhibitor AA861 reduced <italic>Acta2</italic> and <italic>Col1a1</italic> expression in activated HSC. We conclude that melatonin directly suppresses HSC activation via ROR<italic>α</italic>‐mediated inhibition of <italic>Alox5</italic> expression, which provides novel drug targets to treat liver fibrosis.</p> </abstract>