Intracellular Sphingosine 1-Phosphate Contributes to Collagen Expression of Hepatic Myofibroblasts in Human Liver Fibrosis Independent of Its Receptors

Xiu, Lei; Chang, Na; Yang, Le; Liu, Xin; Yang, Lin; Ge, Jingjing; Li, Liying

doi:10.1016/j.ajpath.2014.09.023

Cited by 39 publications

(40 citation statements)

References 52 publications

(58 reference statements)

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“…Similarly, Xiu et al . tested siRNAs targeting SPHK1 in human HSCs46. Consistent with our findings, depletion of SPHK1 did not result in a reduction in COL1A1 mRNA levels compared to a control siRNA; moreover, treatment with N,N-dimethylsphingosine (DMS), an inhibitor of sphingosine kinase, did not lead to COL1A1 mRNA reduction.…”

Section: Discussionsupporting

confidence: 84%

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells

Chen¹,

Newcomb²,

Zhou³

et al. 2017

Sci Rep

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Activation of hepatic stellate cells (HSCs) in response to injury is a key step in hepatic fibrosis, and is characterized by trans-differentiation of quiescent HSCs to HSC myofibroblasts, which secrete extracellular matrix proteins responsible for the fibrotic scar. There are currently no therapies to directly inhibit hepatic fibrosis. We developed a small molecule screen to identify compounds that inactivate human HSC myofibroblasts through the quantification of lipid droplets. We screened 1600 compounds and identified 21 small molecules that induce HSC inactivation. Four hits were tricyclic antidepressants (TCAs), and they repressed expression of pro-fibrotic factors Alpha-Actin-2 (ACTA2) and Alpha-1 Type I Collagen (COL1A1) in HSCs. RNA sequencing implicated the sphingolipid pathway as a target of the TCAs. Indeed, TCA treatment of HSCs promoted accumulation of ceramide through inhibition of acid ceramidase (aCDase). Depletion of aCDase also promoted accumulation of ceramide and was associated with reduced COL1A1 expression. Treatment with B13, an inhibitor of aCDase, reproduced the antifibrotic phenotype as did the addition of exogenous ceramide. Our results show that detection of lipid droplets provides a robust readout to screen for regulators of hepatic fibrosis and have identified a novel antifibrotic role for ceramide.

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Section: Discussionsupporting

confidence: 84%

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells

Chen¹,

Newcomb²,

Zhou³

et al. 2017

Sci Rep

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“…Among the chemokines and inflammatory mediators known to exert potent cellular chemotactic effects, the S1P has been recognized as an important regulator of fibrosis in lung, kidney, heart and skin . Recent reports showed that a SphK1/S1P/S1PR signaling axis was involved in liver injury and fibrosis . SphK inhibitor can reduce angiogenesis in fibrotic mice and block the differentiation from bone marrow‐derived mesenchymal stem cells (BMSCs) to myofibroblasts during liver injury, suggesting that targeting SphK might be a therapy in the treatment of liver fibrosis.…”

mentioning

confidence: 99%

Sphingosine kinase 1 promotes liver fibrosis by preventing miR‐19b‐3p‐mediated inhibition of CCR2

et al. 2018

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Chronic liver disease mediated by activation of hepatic stellate cells (HSCs) and Kupffer cells (KCs) leads to liver fibrosis. Here, we aimed to investigate the molecular mechanism and define the cell type involved in mediating the sphingosine kinase (SphK)1‐dependent effect on liver fibrosis. The levels of expression and activity of SphK1 were significantly increased in fibrotic livers compared with the normal livers in human. SphK1 was coexpressed with a range of HSC/KC markers including desmin, α‐smooth muscle actin (α‐SMA) and F4/80 in fibrotic liver. Deficiency of SphK1 (SphK1−/−) resulted in a marked amelioration of hepatic injury, including transaminase activities, histology, collagen deposition, α‐SMA and inflammation, in CCl4 or bile duct ligation (BDL)‐induced mice. Likewise, treatment with a specific inhibitor of SphK1, 5C, also significantly prevented liver injury and fibrosis in mice induced by CCl4 or BDL. In cellular levels, inhibition of SphK1 significantly blocked the activation and migration of HSCs and KCs. Moreover, SphK1 knockout in KCs reduced the secretion of CCL2, and SphK1 knockout in HSCs reduced C‐C motif chemokine receptor 2 ([CCR2] CCL2 receptor) expression in HSCs. CCL2 in SphK1−/− mice was lower whereas microRNA‐19b‐3p in SphK1−/− mice was higher compared with wild‐type (WT) mice. Furthermore, microRNA‐19b‐3p downregulated CCR2 in HSCs. The functional effect of SphK1 in HSCs on liver fibrosis was further strengthened by the results of animal experiments using a bone marrow transplantation (BMT) method. Conclusion: SphK1 has distinct roles in the activation of KCs and HSCs in liver fibrosis. Mechanistically, SphK1 in KCs mediates CCL2 secretion, and SphK1 in HSCs upregulates CCR2 by downregulation of miR‐19b‐3p. (Hepatology 2018).

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“…In contrast, an important role of S1P1 and S1P3 but not S1P2 in liver fibrosis has been demonstrated in mice16. Furthermore, the contribution of intracellular S1P to liver fibrosis, independent of its receptors, has been recently reported in human17. Although these lines of evidence suggest that S1P plays an important role in pathophysiology of liver fibrosis, the contribution of its receptors to liver fibrosis remains elusive.…”

mentioning

confidence: 99%

Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human

Sato

Ikeda

Uranbileg

et al. 2016

Sci Rep

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The role of sphingosine 1-phosphate (S1P) in liver fibrosis or inflammation was not fully examined in human. Controversy exists which S1P receptors, S1P1 and S1P3 vs S1P2, would be importantly involved in its mechanism. To clarify these matters, 80 patients who received liver resection for hepatocellular carcinoma and 9 patients for metastatic liver tumor were enrolled. S1P metabolism was analyzed in background, non-tumorous liver tissue. mRNA levels of sphingosine kinase 1 (SK1) but not SK2 were increased in livers with fibrosis stages 3–4 compared to those with 0–2 and to normal liver. However, S1P was not increased in advanced fibrotic liver, where mRNA levels of S1P transporter spinster homolog 2 (SPNS2) but not S1P-degrading enzymes were enhanced. Furthermore, mRNA levels of S1P2 but not S1P1 or S1P3 were increased in advanced fibrotic liver. These increased mRNA levels of SK1, SPNS2 and S1P2 in fibrotic liver were correlated with α-smooth muscle actin mRNA levels in liver, and with serum ALT levels. In conclusion, S1P may be actively generated, transported to outside the cells, and bind to its specific receptor in human liver to play a role in fibrosis or inflammation. Altered S1P metabolism in fibrotic liver may be their therapeutic target.

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Intracellular Sphingosine 1-Phosphate Contributes to Collagen Expression of Hepatic Myofibroblasts in Human Liver Fibrosis Independent of Its Receptors

Cited by 39 publications

References 52 publications

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells

Tricyclic Antidepressants Promote Ceramide Accumulation to Regulate Collagen Production in Human Hepatic Stellate Cells

Sphingosine kinase 1 promotes liver fibrosis by preventing miR‐19b‐3p‐mediated inhibition of CCR2

Sphingosine kinase-1, S1P transporter spinster homolog 2 and S1P2 mRNA expressions are increased in liver with advanced fibrosis in human

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