Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.
作者： Isabel Varela-Nieto , Carmen García-Ruiz , José C. Fernández-Checa , Anna Colell , Albert Morales
DOI: 10.1172/JCI19852
关键词:
摘要: 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 downregulation TNF-alpha. The levels mRNA as well MAT I/III protein decreased cultured rat hepatocytes situ generation ceramide from exogenous human placenta ASMase. Hepatocytes lacking ASMase (ASMase-/-) were insensitive TNF-alpha but responsive ASMase-induced MAT1A. In an vivo model lethal hepatitis TNF-alpha, depletion SAM preceded activation caspases 8 3, massive damage, death mice. contrast, minimal hepatic depletion, caspase activation, damage seen ASMase-/- Moreover, therapeutic treatment with abrogated injury, thus rescuing ASMase+/+ mice TNF-alpha-induced lethality. Thus, have demonstrated a new role for failure through MAT1A, maintenance may be useful acute chronic diseases.
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