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PXD046506-1

PXD046506 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleProtein tyrosine phosphatase receptor kappa regulates glycolysis, de novo lipogenesis and promotes hepatocyte metabolic reprogramming in obesity.
DescriptionFat accumulation, de novo lipogenesis, and glycolysis are key contributors to hepatocyte reprogramming and the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD). The molecular mechanisms affected by steatosis and inflammation in the obese states remain unknown. Here we report that obesity leads to dysregulated expression of protein-tyrosine phosphatases (PTPs) in the liver. Protein Tyrosine Phosphatase Receptor Kappa (PTPRK) was increased in hepatocytes by steatosis and inflammation in humans and mice, and positively correlates with PPARγ-induced lipogenic signalling. Mechanistically, PTPRK-PPARγ upregulation by fat accumulation is dependent upon Notch signalling in mouse primary hepatocytes. PTPRK knockout mice have reduced fat accumulation in adipose tissue and liver after exposure to an obesogenic diet. Phosphoproteomic analysis in isolated hepatocytes and hepatic metabolomics identified specific phosphotyrosine residues in fructose-1,6 bisphosphatase-1 and glycolysis regulation as targets of PTPRK. These changes in glycolysis and de novo lipogenesis revealed PTPRK-dependent metabolic reprogramming in hepatocytes. Moreover, hepatoma cell lines showed reduced colony-forming ability after PTPRK silencing in vitro, and PTPRK knockout mice developed smaller tumours after diethylnitrosamine-induced hepatocarcinogenesis in vivo. Computational modelling identified potential PTPRK inhibitors, which selectively reduced PTPRK activity. The compounds decreased glycolytic rates in hepatoma cell lines, PPARγ expression in primary hepatocytes and steatosis in obese mice. In conclusion, our study defines a novel mechanism for the development of MASLD, revealing a key role of PTPRK on hepatic glycolysis regulation with implications in lipid metabolism, and liver tumour development. We propose PTPRK as a potential target for metabolic liver dysfunction, and the identified inhibitors may represent promising candidates for therapy in obesity-associated liver diseases.
HostingRepositoryPRIDE
AnnounceDate2024-10-21
AnnouncementXMLSubmission_2024-10-21_04:39:37.708.xml
DigitalObjectIdentifierhttps://dx.doi.org/10.6019/PXD046506
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportSupported dataset by repository
PrimarySubmitterThibaut Vignane
SpeciesList scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationListphosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
InstrumentOrbitrap Eclipse
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-10-30 10:07:50ID requested
12024-10-21 04:39:38announced
Publication List
10.6019/PXD046506;
Keyword List
submitter keyword: MASLD, obesity, phosphoproteomic,Liver, PTPRK
Contact List
Milos Filipovic
contact affiliationSULFAGING group, Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., DORTMUND, GERMANy
contact emailmilos.filipovic@isas.de
lab head
Thibaut Vignane
contact affiliationLeibniz-Institut für Analytische Wissenschaften - ISAS - eV
contact emailthibaut.vignane@isas.de
dataset submitter
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Dataset FTP location
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