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

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 hyperphos-phorylation signature consistent with casein kinase 2a (CK2a) and AKT1 activa-tion, 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 pathophys-iological and therapeutic implications.

Automated summary

Methionine adenosyltransferase 1a (MAT1A) is responsible for hepatic S-adenosyl-L-methionine (SAMe) biosynthesis. Mat1a(-/-) mice develop nonalcoholic steatohepatitis (NASH) due to hepatic SAMe depletion, which can be reversed with SAMe administration. Temporal alterations in the proteome/phosphoproteome were observed in pre-disease and NASH Mat1a(-/-) mice, with persistent alterations in lipid metabolism proteins. Hyperphosphorylation signature consistent with CK2a and AKT1 activation was found in both pre-disease and NASH livers, which could be normalized with SAMe administration. A metabolomic signature resembling Mat1a(-/-) mice was discovered in human NAFLD with the M-subtype. These findings have important implications for the pathophysiology and treatment of NAFLD.