Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency

Aaron E Robinson; Aleksandra Binek; Komal Ramani; Niveda Sundararaman; Lucía Barbier-Torres; Ben Murray; Vidya Venkatraman; Simion Kreimer; Angela Mc Ardle; Mazen Noureddin; David Fernández-Ramos; Fernando Lopitz-Otsoa; Virginia Gutiérrez de Juan; Oscar Millet; José M Mato; Shelly C Lu; Jennifer E Van Eyk

doi:10.1016/j.isci.2023.105987

Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency

iScience. 2023 Jan 14;26(2):105987. doi: 10.1016/j.isci.2023.105987. eCollection 2023 Feb 17.

Authors

Aaron E Robinson¹, Aleksandra Binek¹, Komal Ramani², Niveda Sundararaman¹, Lucía Barbier-Torres², Ben Murray², Vidya Venkatraman¹, Simion Kreimer¹, Angela Mc Ardle¹, Mazen Noureddin², David Fernández-Ramos³, Fernando Lopitz-Otsoa³, Virginia Gutiérrez de Juan³, Oscar Millet³, José M Mato³, Shelly C Lu², Jennifer E Van Eyk¹

Affiliations

¹ Advanced Clinical Biosystems Research Institute, The Smidt Heart Institute, Cedars Sinai Medical Center, Advanced Health Sciences Pavilion, 127 S. San Vicente Blvd, Room 9302, Los Angeles, CA 90048, USA.
² Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Davis Building, Room 2097, Los Angeles, CA 90048, USA.
³ CIC bioGUNE, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd), Technology Park of Bizkaia, 48160 Derio, Bizkaia, Spain.

Abstract

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.

Keywords: Human metabolism; Molecular biology; Proteomics.

Abstract

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