Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.
Animals
Blood Platelets
/ drug effects
Body Weight
/ drug effects
Cytokines
/ metabolism
Cytoplasmic Granules
/ drug effects
Endothelium
/ drug effects
Hepatocytes
/ drug effects
Humans
Hyaluronan Receptors
/ metabolism
Hyaluronic Acid
/ metabolism
Kupffer Cells
/ drug effects
Liver
/ drug effects
Liver Neoplasms
/ blood
Mice, Transgenic
Non-alcoholic Fatty Liver Disease
/ blood
Platelet Aggregation
/ drug effects
Platelet Aggregation Inhibitors
/ pharmacology
Platelet Count
Platelet Glycoprotein GPIb-IX Complex
/ metabolism
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
04 2019
04 2019
Historique:
received:
14
09
2017
accepted:
28
01
2019
pubmed:
3
4
2019
medline:
11
5
2019
entrez:
3
4
2019
Statut:
ppublish
Résumé
Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.
Identifiants
pubmed: 30936549
doi: 10.1038/s41591-019-0379-5
pii: 10.1038/s41591-019-0379-5
doi:
Substances chimiques
Cytokines
0
Hyaluronan Receptors
0
Platelet Aggregation Inhibitors
0
Platelet Glycoprotein GPIb-IX Complex
0
adhesion receptor
0
Hyaluronic Acid
9004-61-9
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
641-655Subventions
Organisme : Medical Research Council
ID : MC_PC_14123
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0700301
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300101
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0300102
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/M009157/1
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0400496
Pays : United Kingdom
Organisme : Medical Research Council
ID : MC_U120097114
Pays : United Kingdom
Organisme : Cancer Research UK
ID : 26813
Pays : United Kingdom
Organisme : Medical Research Council
ID : G0802577
Pays : United Kingdom
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : CommentIn
Type : ErratumIn
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