Melatonin suppresses activation of hepatic stellate cells through ROR alpha-mediated inhibition of 5-lipoxygenase

Shiva Shajari, Almudena Laliena, Janette Heegsma, Maria Jesus Tunon, Han Moshage, Klaas Nico Faber*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

25 Citations (Scopus)

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 (alpha SMA, Acta2), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor-related orphan receptor-alpha (ROR alpha/Nr1f1) was expressed in quiescent and activated HSC, while the membranous melatonin receptors (Mtrn1a and Mtrn1b) were not. The synthetic ROR alpha agonist SR1078 more potently suppressed Col1a1 and alpha Sma expression, HSC proliferation, and lipid droplet loss, while the ROR alpha 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 ROR alpha-mediated inhibition of Alox5 expression, which provides novel drug targets to treat liver fibrosis.

Original languageEnglish
Pages (from-to)391-401
Number of pages11
JournalJournal of Pineal Research
Volume59
Issue number3
DOIs
Publication statusPublished - Oct-2015

Keywords

  • 5-lipoxygenase
  • hepatic stellate cell
  • hepatic stellate cell activation
  • liver fibrosis
  • melatonin
  • proliferation
  • retinoic acid receptor-related orphan receptor alpha
  • PROSTATE-CANCER CELLS
  • LIVER FIBROSIS
  • ANTIOXIDANT ENZYMES
  • CHOLESTATIC RATS
  • OXIDATIVE DAMAGE
  • GENE-EXPRESSION
  • SEPTIC SHOCK
  • VIRAL ORIGIN
  • GROWTH
  • PROLIFERATION

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