TY - JOUR
T1 - Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency
AU - Robinson, Aaron E.
AU - Binek, Aleksandra
AU - Ramani, Komal
AU - Sundararaman, Niveda
AU - Barbier-Torres, Lucía
AU - Murray, Ben
AU - Venkatraman, Vidya
AU - Kreimer, Simion
AU - Ardle, Angela Mc
AU - Noureddin, Mazen
AU - Fernández-Ramos, David
AU - Lopitz-Otsoa, Fernando
AU - Gutiérrez de Juan, Virginia
AU - Millet, Oscar
AU - Mato, José M.
AU - Lu, Shelly C.
AU - Van Eyk, Jennifer E.
N1 - Funding Information:
Paraffin-embedded liver tissues were stained with hematoxylin and eosin (H&E) using the core services provided by the liver histology core of the University of Southern California research center for liver diseases (NIH grant P30 DK048522).
Funding Information:
This work was supported by US National Institutes of Health (NIH) Grant R01DK123763 (S.C.L., K.R., J.M.M., and J.E.V.E.), Agencia Estatal de Investigación, Spain Grants MINECO SAF 2017-88041-R , ISCiii PIE14/00031 CIBERehd-ISCiii , and Severo Ochoa Excellence Accreditation SEV-2016-0644 (J.M.M.) and the Cedars-Sinai Proteomic and Metabolomic Core Facility .
Publisher Copyright:
© 2023
PY - 2023/2/17
Y1 - 2023/2/17
N2 - Methionine adenosyltransferase 1a (MAT1A) is responsible for hepatic S-adenosyl-L-methionine (SAMe) biosynthesis. Mat1a−/− mice have hepatic SAMe depletion, develop nonalcoholic steatohepatitis (NASH) which is reversed with SAMe administration. We examined temporal alterations in the proteome/phosphoproteome in pre-disease and NASH Mat1a−/− mice, effects of SAMe administration, and compared to human nonalcoholic fatty liver disease (NAFLD). Mitochondrial and peroxisomal lipid metabolism proteins were altered in pre-disease mice and persisted in NASH Mat1a−/− mice, which exhibited more progressive alterations in cytoplasmic ribosomes, ER, and nuclear proteins. A common mechanism found in both pre-disease and NASH livers was a hyperphosphorylation signature consistent with casein kinase 2α (CK2α) and AKT1 activation, which was normalized by SAMe administration. This was mimicked in human NAFLD with a metabolomic signature (M-subtype) resembling Mat1a−/− mice. In conclusion, we have identified a common proteome/phosphoproteome signature between Mat1a−/− mice and human NAFLD M-subtype that may have pathophysiological and therapeutic implications.
AB - Methionine adenosyltransferase 1a (MAT1A) is responsible for hepatic S-adenosyl-L-methionine (SAMe) biosynthesis. Mat1a−/− mice have hepatic SAMe depletion, develop nonalcoholic steatohepatitis (NASH) which is reversed with SAMe administration. We examined temporal alterations in the proteome/phosphoproteome in pre-disease and NASH Mat1a−/− mice, effects of SAMe administration, and compared to human nonalcoholic fatty liver disease (NAFLD). Mitochondrial and peroxisomal lipid metabolism proteins were altered in pre-disease mice and persisted in NASH Mat1a−/− mice, which exhibited more progressive alterations in cytoplasmic ribosomes, ER, and nuclear proteins. A common mechanism found in both pre-disease and NASH livers was a hyperphosphorylation signature consistent with casein kinase 2α (CK2α) and AKT1 activation, which was normalized by SAMe administration. This was mimicked in human NAFLD with a metabolomic signature (M-subtype) resembling Mat1a−/− mice. In conclusion, we have identified a common proteome/phosphoproteome signature between Mat1a−/− mice and human NAFLD M-subtype that may have pathophysiological and therapeutic implications.
KW - Human metabolism
KW - Molecular biology
KW - Proteomics
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U2 - 10.1016/j.isci.2023.105987
DO - 10.1016/j.isci.2023.105987
M3 - Article
C2 - 36756374
AN - SCOPUS:85147205035
SN - 2589-0042
VL - 26
SP - 105987
JO - iScience
JF - iScience
IS - 2
M1 - 105987
ER -