Deletion of platelet-derived growth factor receptor β suppresses tumorigenesis in metabolic dysfunction-associated steatohepatitis (MASH) mice with diabetes.
Animals
Receptor, Platelet-Derived Growth Factor beta
/ metabolism
Mice
Carcinogenesis
/ genetics
Mice, Knockout
Humans
MicroRNAs
/ genetics
Fatty Liver
/ metabolism
Disease Models, Animal
Male
Platelet-Derived Growth Factor
/ metabolism
Liver
/ metabolism
Hepatic Stellate Cells
/ metabolism
Signal Transduction
Diabetes Mellitus, Experimental
/ metabolism
Hepatic stellate cells (HSC)
Metabolic dysfunction-associated steatohepatitis (MASH)
MicroRNA
Platelet-derived growth factor (PDGF)
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
11 Oct 2024
11 Oct 2024
Historique:
received:
28
05
2024
accepted:
08
10
2024
medline:
12
10
2024
pubmed:
12
10
2024
entrez:
11
10
2024
Statut:
epublish
Résumé
The platelet-derived growth factor (PDGF) family contributes to the progression of steatohepatitis; however, changes in and the characteristics of isoform-specific expression remain unclear. Since diabetes is a major driver of metabolic dysfunction-associated steatohepatitis (MASH), we characterized the mouse model of diabetic MASH (dMASH) by focusing on PDGF signaling. Pdgfa-d expression was markedly higher in hepatic stellate cells among flow-sorted cells in control mice and also increased in dMASH. In contrast, a reanalysis of human single-cell RNA-Seq data showed the distinct distribution of each PDGF isoform with disease progression. Furthermore, inflammation and fibrosis in the liver were less severe in diabetic MASH using tamoxifen-induced PDGF receptor β (PDGFRβ)-deficient mice (KO) than in control dMASH using floxed mice (FL) at 12 weeks old. Despite the absence of tumors, the expression of tumor-related genes was lower in KO than in FL. Tumorigenesis was significantly lower in 20-week-old KO. An Ingenuity Pathway Analysis of differentially expressed miRNA between FL and KO identified functional networks associated with hepatotoxicity and cancer. Therefore, PDGFRβ signals play important roles in the progression of steatohepatitis and tumorigenesis in MASH, with the modulation of miRNA expression posited as a potential underlying mechanism.
Identifiants
pubmed: 39394459
doi: 10.1038/s41598-024-75713-6
pii: 10.1038/s41598-024-75713-6
doi:
Substances chimiques
Receptor, Platelet-Derived Growth Factor beta
EC 2.7.10.1
MicroRNAs
0
Platelet-Derived Growth Factor
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
23829Subventions
Organisme : Japan Society for the Promotion of Science
ID : JP21K08549
Organisme : Japan Society for the Promotion of Science
ID : JP24K02855
Organisme : Japan Society for the Promotion of Science
ID : 23H02957
Organisme : Moonshot Research and Development Program
ID : JPMJMS2021
Informations de copyright
© 2024. The Author(s).
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