PXD048073

PXD048073 is an original dataset announced via ProteomeXchange.

Title	Glycogen Synthase Kinase 3 Activity Enhances Liver Inflammation in Metabolic Dysfunction Associated Steatohepatitis
Description	Metabolic Dysfunction Associated Steatohepatitis (MASH) is characterized by excess circulating toxic lipids, hepatic steatosis, and liver inflammation. Monocyte adhesion to the liver sinusoidal endothelial cells (LSEC) and transendothelial migration (TEM) are crucial in the inflammatory process. LSEC under lipotoxic stress develops a pro-inflammatory phenotype known as endotheliopathy. However, the mediators of endotheliopathy remain obscure. Primary mouse LSEC isolated from C57BL/6J mice on chow or MASH-inducing diets rich in fat, fructose, and cholesterol (FFC) were subjected to multi-omics profiling. Mice with established MASH, due to a choline-deficient high-fat diet (CDHFD) or FFC diet, were treated with two structurally distinct GSK3 inhibitors [LY2090314, elraglusib (9-ING-41)]. Integrated pathway analysis of mouse LSEC proteome and transcriptome indicates that leukocyte TEM and focal adhesion are major pathways altered in MASH. Kinome profiling of the LSEC phospho-proteome identified GSK3β as the major kinase hub in MASH. GSK3β activating phosphorylation was increased in primary human LSEC treated with the toxic lipid palmitate and in human MASH. Palmitate upregulated the expression of C-X-C motif chemokine ligand 2, intracellular adhesion molecule 1, and phosphorylated focal adhesion kinase, via a GSK3-dependant mechanism. Congruently, the adhesive and transendothelial migratory capacities of primary human neutrophils and THP-1 monocytes through LSEC monolayer under lipotoxic stress were reduced by GSK3 inhibition. Treatment with the GSK3 inhibitors LY2090314 and elraglusib ameliorated liver inflammation, injury, and fibrosis in FFC and CDHFD-fed mice, respectively. Immunophenotyping of intrahepatic leukocytes from CDHFD-fed mice treated with elraglusib using cytometry by the time of flight showed reduced proinflammatory monocyte-derived macrophages and monocyte-derived dendritic cells infiltration.GSK3 inhibition attenuates lipotoxicity-induced LSEC endotheliopathy and may serve as a potential therapeutic strategy in human MASH.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_06:46:29.113.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Khaled Warasnhe
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-12-22 01:25:22	ID requested
1	2024-06-22 08:33:04	announced
⏵ 2	2024-10-22 06:46:32	announced	2024-10-22: Updated project metadata.

10.1016/j.jhepr.2024.101073;

Khoury M, Guo Q, Furuta K, Correia C, Meroueh C, Kim Lee HS, Warasnhe K, Valenzuela-P, é, rez L, Mazar AP, Kim I, Noh YK, Holmes H, Romero MF, Sussman CR, Pavelko KD, Islam S, Bamidele AO, Hirsova P, Li H, Ibrahim SH, Glycogen synthase kinase 3 activity enhances liver inflammation in MASH. JHEP Rep, 6(6):101073(2024) [pubmed]

submitter keyword: LSEC,Mouse, Hepatosteatosis, Liver

Samar H Ibrahim
contact affiliation	Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
contact email	ibrahim.samar@mayo.edu
lab head
Khaled Warasnhe
contact affiliation	Department of Gastroenterology and Hepatology Mayo Clinic Rochester, MN
contact email	warasnhe.khaled@mayo.edu
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/06/PXD048073

PRIDE project URI

• PRIDE
  1. PXD048073
     1. Label: PRIDE project
     2. Name: Glycogen Synthase Kinase 3 Activity Enhances Liver Inflammation in Metabolic Dysfunction Associated Steatohepatitis