Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Marí, M. et al.

Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.

S-adenosyl-L-methionine (SAM) is synthesized by methionine adenosyltransferases (MATs). Ablation of the liver-specific MAT1A gene results in liver neoplasia and sensitivity to oxidant injury. Here we show that acidic sphingomyelinase (ASMase) mediates the downregulation of MAT1A by TNF-alpha. The levels of MAT1A mRNA as well as MAT I/III protein decreased in cultured rat hepatocytes by in situ generation of ceramide from exogenous human placenta ASMase. Hepatocytes lacking the ASMase gene (ASMase-/-) were insensitive to TNF-alpha but were responsive to exogenous ASMase- induced downregulation of MAT1A. In an in vivo model of lethal hepatitis by TNF-alpha, depletion of SAM preceded activation of caspases 8 and 3, massive liver damage, and death of the mice. In contrast, minimal hepatic SAM depletion, caspase activation, and liver damage were seen in ASMase-/- mice. Moreover, therapeutic treatment with SAM abrogated caspase activation and liver injury, thus rescuing ASMase+/+ mice from TNF-alpha-induced lethality. Thus, we have demonstrated a new role for ASMase in TNF-alpha- induced liver failure through downregulation of MAT1A, and maintenance of SAM may be useful in the treatment of acute and chronic liver diseases.[1]

References

Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis. Marí, M., Colell, A., Morales, A., Pañeda, C., Varela-Nieto, I., García-Ruiz, C., Fernández-Checa, J.C. J. Clin. Invest. (2004) [Pubmed]

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