RT info:eu-repo/semantics/preprint
T1 Inhibition of the SphK1/S1P signaling pathway by melatonin in mice with liver fibrosis and human hepatic stellate cells
A1 González-Fernández, Bárbara
A1 Sánchez, Diana I.
A1 Crespo, Irene
A1 San-Miguel, Beatriz
A1 Álvarez, Marcelino
A1 Tuñón González, María Jesús
A1 González Gallego, Javier
A2 Otros
K1 Medicina. Salud
K1 Hepatic stellate cells
K1 Liver fibrosis
K1 Melatonin
K1 Sphingolipids
AB The sphingosine kinase 1/sphingosine 1-phosphate (SphK1/S1P) system is involved indifferent pathological processes, including fibrogenesis. Melatonin abrogates activation ofhepatic stellate cells (HSCs) and attenuates different profibrogenic pathways in animalmodels of fibrosis, but it is unknown if protection associates with its inhibitory effect on theSphK1/S1P axis. Mice in treatment groups received carbon tetrachloride (CCl4) 5 μL/g bodywt 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 followingCCl4 treatment, liver mRNA levels, protein concentration and immunohistochemical labellingfor SphK1 increased significantly. S1P production, and expression of S1P receptor (S1PR)1,S1PR3 and acid sphingomyelinase (ASMase) were significantly elevated. However, there wasa 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 inhibitedS1P production, lowered expression of SphK1, S1PR1, SP1R3 and ASMase, and increasedexpression of S1PL. Melatonin induced a reversal of activated human HSCs cell line LX2, asevidenced by a reduction in α-SMA, TGF-β, and Col I expression. Melatonin-treated cellsalso exhibited an inhibition of the SphK1/S1P axis. Antifibrogenic effect of SphK1 inhibitionwas confirmed by treatment of LX2 cells with PF543. Abrogation of the lipid signalingpathway by the indole reveals novel molecular pathways that may account for the protectiveeffect of melatonin in liver fibrogenesis
PB Wiley
YR 2016
FD 2016-12-19
LK http://hdl.handle.net/10612/5690
UL http://hdl.handle.net/10612/5690
NO BioFactors, 2016
NO 30 p.
DS BULERIA. Repositorio Institucional de la Universidad de León
RD 18-abr-2024