PXD046506

PXD046506 is an original dataset announced via ProteomeXchange.

Title	Protein tyrosine phosphatase receptor kappa regulates glycolysis, de novo lipogenesis and promotes hepatocyte metabolic reprogramming in obesity.
Description	Fat 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.
HostingRepository	PRIDE
AnnounceDate	2024-10-21
AnnouncementXML	Submission_2024-10-21_04:39:37.708.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD046506
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Thibaut Vignane
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2023-10-30 10:07:50	ID requested
⏵ 1	2024-10-21 04:39:38	announced

10.6019/PXD046506;

submitter keyword: MASLD, obesity, phosphoproteomic,Liver, PTPRK

Milos Filipovic
contact affiliation	SULFAGING group, Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V., DORTMUND, GERMANy
contact email	milos.filipovic@isas.de
lab head
Thibaut Vignane
contact affiliation	Leibniz-Institut für Analytische Wissenschaften - ISAS - eV
contact email	thibaut.vignane@isas.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD046506
     1. Label: PRIDE project
     2. Name: Protein tyrosine phosphatase receptor kappa regulates glycolysis, de novo lipogenesis and promotes hepatocyte metabolic reprogramming in obesity.