Hyperphosphorylation of hepatic proteome characterizes nonalcoholic fatty liver disease in S-adenosylmethionine deficiency
Aaron Robinson, Aleksandra Binek, Komal Ramani, Niveda Sundararaman, Lucía Barbier‐Torres, Ben J. Murray, Vidya Venkatraman, Simion Kreimer, Angela Mc Ardle, Mazen Noureddin, David Fernández‐Ramos, Fernando Lopitz‐Otsoa, Virginia Gutiérrez de Juan, Óscar Millet, José M. Mato, Shelly C. Lu, Jennifer E. Van Eyk
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.