In:
Journal of Pineal Research, Wiley, Vol. 59, No. 3 ( 2015-10), p. 391-401
Kurzfassung:
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 ( COL 1 A 1). 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 C ol1a1 and alpha‐smooth muscle actin ( α SMA , A cta2 ), as well as HSC proliferation and loss of lipid droplets. The nuclear melatonin sensor retinoic acid receptor‐related orphan receptor‐alpha ( ROR α / N r1f1 ) was expressed in quiescent and activated HSC , while the membranous melatonin receptors ( M trn1a and M trn1b ) were not. The synthetic ROR α agonist SR 1078 more potently suppressed C ol1a1 and α S ma expression, HSC proliferation, and lipid droplet loss, while the ROR α antagonist SR 1001 blocked the antifibrotic features of melatonin. Melatonin and SR 1078 inhibited the expression of A lox5 , encoding 5‐lipoxygenase (5‐ LO ). The pharmacological 5‐ LO inhibitor AA 861 reduced A cta2 and C ol1a1 expression in activated HSC . We conclude that melatonin directly suppresses HSC activation via ROR α ‐mediated inhibition of A lox5 expression, which provides novel drug targets to treat liver fibrosis.
Materialart:
Online-Ressource
ISSN:
0742-3098
,
1600-079X
DOI:
10.1111/jpi.2015.59.issue-3
Sprache:
Englisch
Verlag:
Wiley
Publikationsdatum:
2015
ZDB Id:
2027992-9
