PXD022122

PXD022122 is an original dataset announced via ProteomeXchange.

Title	Global Hyper-Phosphorylation Characterizes Liver Disease Progression in Methionine Adenosyltransferase 1A Knockout Mice
Description	Methionine adenosyltransferase 1a (Mat1a) is responsible for hepatic biosynthesis of S-adenosyl-L-methionine (SAMe), the principal cellular methyl donor. Mat1a -/- mice have decreased hepatic SAMe levels, and spontaneously develop nonalcoholic steatohepatitis (NASH) which can be reversed with exogenous SAMe administration. The main goals of this study were to: (1) study the proteome and phospho-proteome at different stages in the progression of the Mat1a -/- NASH model to gain insight into the temporal order of altered pathways associated with disease progression, (2) determine the effect SAMe administration on the liver proteome and phospho-proteome in Mat1a -/- mice, and (3) determine if human NASH have a phosphorylation signature similar to the Mat1a -/- NASH model. At an early stage in the disease process, before histological NASH is present, Mat1a -/- mice livers have significantly decreased levels of protein phosphatases and alterations in proteins involved in both mitochondrial and peroxisomal lipid metabolism compared to wild-type littermates. These animals are globally hyper-phosphorylated with 90% of statistically significant phospho-peptides increased and a phospho-proteomics signature consistent with casein kinase 2α (CK2α) and AKT1 activation. By the time Mat1a -/- mice have developed NASH, the proteome from other organelles are also altered, including cytoplasmic ribosomes, endoplasmic reticulum proteins, and nuclear proteins. Additionally, proteins from Mat1a -/- NASH livers are globally hyper-phosphorylated with over 75% of statistically significant phospho-peptides increased and share a similar CK2α and AKT1 activation signature as found in pre-disease Mat1a -/- livers. SAMe administration in Mat1a -/- mice with NASH normalized the CK2α and AKT1 hyper-phosphorylation signature in addition to the altered cellular compartments including the mitochondria, endoplasmic reticulum, ribosome, and peroxisome. Performing similar analysis on liver samples from NASH patients with the M-subtype metabolomics signature (Mat1a -/--like), we observed hyper-phosphorylation consistent with CK2α activation that is similar to Mat1a -/- NASH livers. Our findings elucidate the temporal order of proteomic and phospho-proteomic alterations associated with disease progression in the Mat1a -/- NASH model as well as those which were responsive to SAMe administration. Phospho-proteomics analysis alone has foreshadowed the hyperactive signaling pathways (CK2α and AKT1) in the Mat1a -/- NASH model before histologically visible disease. Importantly, human NASH patients that have the M-subtype serum metabolomics also have a protein hyper-phosphorylation signature in their livers similar to the Mat1a -/- NASH model. Together, these cohorts of animals at different stages of NASH development allow us to not only determine the proteome, protein phosphorylation, and pathways altered in the disease progression of the Mat1a -/- NASH model but also the effect of SAMe administration during the development of NASH.
HostingRepository	PanoramaPublic
AnnounceDate	2026-06-12
AnnouncementXML	Submission_2026-06-12_15:05:57.933.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	supported by repository but incomplete data and/or metadata
PrimarySubmitter	Aaron Robinson
SpeciesList	scientific name: Mus musculus; NCBI TaxID: 10090; scientific name: Homo sapiens; NCBI TaxID: 9606;
ModificationList	Phospho; Carbamidomethyl; Oxidation
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2020-10-21 21:17:49	ID requested
⏵ 1	2026-06-12 15:05:58	announced

Robinson AE, Binek A, Ramani K, Sundararaman N, Barbier-Torres L, Murray B, Venkatraman V, Kreimer S, Ardle AM, Noureddin M, Fern, á, ndez-Ramos D, Lopitz-Otsoa F, Guti, é, rrez de Juan V, Millet O, Mato JM, Lu SC, Van Eyk JE, Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency. iScience, 26(2):105987(2023) [pubmed]

submitter keyword: NASH, liver, phospho, DIA, DDA, AKT1, CK2, Nonalcoholic Steatohepatitis

Jennifer Van Eyk
contact affiliation	Cedars Sinai Medical Center
contact email	jennifer.vaneyk@cshs.org
lab head
Aaron Robinson
contact affiliation	Cedars Sinai Medical Center
contact email	aaron.robinson@cshs.org
dataset submitter

Panorama Public dataset URI