Exogenous S1P via S1P receptor 2 induces CTGF expression through Src-RhoA-ROCK-YAP pathway in hepatic stellate cells.

Hepatic Stellate Cells / metabolism Connective Tissue Growth Factor / metabolism Lysophospholipids / metabolism Humans rho-Associated Kinases / metabolism Sphingosine / analogs & derivatives Signal Transduction YAP-Signaling Proteins / metabolism rhoA GTP-Binding Protein / metabolism Transcription Factors / metabolism Sphingosine-1-Phosphate Receptors / metabolism Cell Line Liver Cirrhosis / metabolism src-Family Kinases / metabolism Adaptor Proteins, Signal Transducing / metabolism Receptors, Lysosphingolipid / metabolism Collagen Type I / metabolism Hippo Signaling Pathway
Cytoskeletal rearrangement Hepatic fibrosis Hepatic stellate cell Hippo-YAP signaling pathway Sphingosine 1-phosphate (S1P) Sphingosine 1-phosphate receptor (S1PR)

Journal

Molecular biology reports
ISSN: 1573-4978
Titre abrégé: Mol Biol Rep
Pays: Netherlands
ID NLM: 0403234

Informations de publication

Date de publication:
02 Sep 2024
Historique:
received: 19 03 2024
accepted: 14 08 2024
medline: 2 9 2024
pubmed: 2 9 2024
entrez: 2 9 2024
Statut: epublish

Résumé

Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial. In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation. Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor. Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis.

Sections du résumé

BACKGROUND BACKGROUND
Hepatic fibrosis, a prevalent chronic liver condition, involves excessive extracellular matrix production associated with aberrant wound healing. Hepatic stellate cells (HSCs) play a pivotal role in liver fibrosis, activated by inflammatory factors such as sphingosine 1-phosphate (S1P). Despite S1P's involvement in fibrosis, its specific role and downstream pathway in HSCs remain controversial.
METHODS METHODS
In this study, we investigated the regulatory role of S1P/S1P receptor (S1PR) in Hippo-YAP activation in both LX-2 cell lines and primary HSCs. Real-time PCR, western blot, pharmacological inhibitors, siRNAs, and Rho activity assays were adopted to address the molecular mechanisms of S1P mediated YAP activation.
RESULTS RESULTS
Serum and exogenous S1P significantly increased the expression of YAP target genes in HSCs. Pharmacologic inhibitors and siRNA-mediated knockdowns of S1P receptors showed S1P receptor 2 (S1PR2) as the primary mediator for S1P-induced CTGF expression in HSCs. Results using siRNA-mediated knockdown, Verteporfin, and Phospho-Tag immunoblots showed that S1P-S1PR2 signaling effectively suppressed the Hippo kinases cascade, thereby activating YAP. Furthermore, S1P increased RhoA activities in cells and ROCK inhibitors effectively blocked CTGF induction. Cytoskeletal-perturbing reagents were shown to greatly modulate CTGF induction, suggesting the important role of actin cytoskeleton in S1P-induced YAP activation. Exogeneous S1P treatment was enough to increase the expression of COL1A1 and α-SMA, that were blocked by YAP specific inhibitor.
CONCLUSIONS CONCLUSIONS
Our data demonstrate that S1P/S1PR2-Src-RhoA-ROCK axis leads to Hippo-YAP activation, resulting in the up-regulation of CTGF, COL1A1 and α-SMA expression in HSCs. Therefore, S1PR2 may represent a potential therapeutic target for hepatic fibrosis.

Identifiants

DOI: 10.1007/s11033-024-09868-w PMID: 39222158
pubmed: 39222158
doi: 10.1007/s11033-024-09868-w
pii: 10.1007/s11033-024-09868-w
doi:

Substances chimiques

Connective Tissue Growth Factor 139568-91-5
Lysophospholipids 0
sphingosine 1-phosphate 26993-30-6
rho-Associated Kinases EC 2.7.11.1
Sphingosine NGZ37HRE42
YAP-Signaling Proteins 0
rhoA GTP-Binding Protein EC 3.6.5.2
CCN2 protein, human 0
Transcription Factors 0
Sphingosine-1-Phosphate Receptors 0
S1PR2 protein, human 0
src-Family Kinases EC 2.7.10.2
Adaptor Proteins, Signal Transducing 0
Receptors, Lysosphingolipid 0
YAP1 protein, human 0
RHOA protein, human 124671-05-2
Collagen Type I 0

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

950

Subventions

Organisme : Jongwha Kim
ID : 2017R1D1A1B0403430314
Organisme : Yong-Han Paik
ID : NRF-2017R1A2B2002735

Informations de copyright

© 2024. The Author(s), under exclusive licence to Springer Nature B.V.

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Auteurs

Suhyun Park (S)

Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea.

Jonghwa Kim (J)

Samsung Medical Center, 81 Irwon- Ro, Gangnam-Gu, Seoul, 06351, South Korea. jh7289.kim@samsung.com.

Sera Yang (S)

Samsung Medical Center, 81 Irwon- Ro, Gangnam-Gu, Seoul, 06351, South Korea.

So Hee Kang (SH)

Samsung Medical Center, 81 Irwon- Ro, Gangnam-Gu, Seoul, 06351, South Korea.

Wonseok Kang (W)

Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea.
Samsung Medical Center, 81 Irwon- Ro, Gangnam-Gu, Seoul, 06351, South Korea.

Yong-Han Paik (YH)

Department of Health Science and Technology, SAIHST, Sungkyunkwan University, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea. yh.paik@skku.edu.
Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-Ro, Gangnam-Gu, Seoul, 06351, South Korea. yh.paik@skku.edu.
Samsung Medical Center, 81 Irwon- Ro, Gangnam-Gu, Seoul, 06351, South Korea. yh.paik@skku.edu.

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Classifications MeSH

questionsmedicales.fr › Cellules › Cellules étoilées du foie › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Facteurs biologiques › Protéines et peptides de signalisation intercellulaire › Protéines CCN de signalisation intercellulaire › Facteur de croissance du tissu conjonctif › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Lipides › Lipides membranaires › Phospholipides › Glycérophosphate › Acides phosphatidiques › Lysophospholipides › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-Serine-Threonine Kinases › rho-Associated Kinases › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Composés chimiques organiques › Amines › Aminoalcools › Sphingosine › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Protéines de signalisation YAP › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines G › Protéines G monomériques › Protéines G rho › Protéine G RhoA › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Récepteurs aux lysophospholipides › Récepteurs aux lysosphingolipides › Récepteurs de la sphingosine-1-phosphate › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Cellules › Cellules cultivées › Lignée cellulaire › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Fibrose › Cirrhose du foie › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protein-tyrosine kinases › src-Family kinases › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Protéines adaptatrices de la transduction du signal › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs couplés aux protéines G › Récepteurs aux lysophospholipides › Récepteurs aux lysosphingolipides › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Scléroprotéines › Protéines de la matrice extracellulaire › Collagène › Collagènes fibrillaires › Collagène de type I › Exogenous S1P via S1P receptor 2 induces CTGF...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Voie de signalisation Hippo › Exogenous S1P via S1P receptor 2 induces CTGF...