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Título
Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells
Autor
Facultad/Centro
Área de conocimiento
Datos de la obra
BioFactors, 2016
Editor
Wiley
Fecha
2016-01-23
Zusammenfassung
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 body
wt i.p. twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/day i.p,
beginning two weeks after the start of CCl4 administration. At both 4 and 6 weeks following
CCl4 treatment, 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
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