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J Clin Invest. 2004 Mar;113(6):895-904.

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

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1
Liver Unit, Institut de Malalties Digestives, Hospital Clínic i Provincial, Instituto Investigaciones Biomédicas August Pi i Sunyer, Barcelona, Spain.

Abstract

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.

PMID:
15067322
PMCID:
PMC362116
DOI:
10.1172/JCI19852
[Indexed for MEDLINE]
Free PMC Article
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