Hyaluronan synthase 2-mediated hyaluronan production mediates Notch1 activation and liver fibrosis.
Journal
Science translational medicine
ISSN: 1946-6242
Titre abrégé: Sci Transl Med
Pays: United States
ID NLM: 101505086
Informations de publication
Date de publication:
12 06 2019
12 06 2019
Historique:
received:
24
04
2018
accepted:
14
05
2019
entrez:
14
6
2019
pubmed:
14
6
2019
medline:
1
7
2020
Statut:
ppublish
Résumé
Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were reduced in mice lacking HAS2 in hepatic stellate cells (HSCs), whereas mice overexpressing HAS2 had exacerbated liver fibrosis. HAS2 was transcriptionally up-regulated by transforming growth factor-β through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4 (TLR4), and newly identified downstream effector Notch1. Inhibition of HA synthesis by 4-methylumbelliferone reduced HSC activation and liver fibrosis in mice. Our study provides evidence that HAS2 actively synthesizes HA in HSCs and that it promotes HSC activation and liver fibrosis through Notch1. Targeted HA inhibition may have potential to be an effective therapy for liver fibrosis.
Identifiants
pubmed: 31189722
pii: 11/496/eaat9284
doi: 10.1126/scitranslmed.aat9284
pmc: PMC6589184
mid: NIHMS1036391
pii:
doi:
Substances chimiques
Hyaluronan Receptors
0
Toll-Like Receptor 4
0
Hymecromone
3T5NG4Q468
Hyaluronic Acid
9004-61-9
Hyaluronan Synthases
EC 2.4.1.212
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NIAAA NIH HHS
ID : R21 AA025841
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI052201
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL122068
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK085252
Pays : United States
Organisme : NIAAA NIH HHS
ID : R01 AA027036
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL108793
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK107288
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL134637
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.
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