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Title

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

AuthorsMarí, Montserrat ; Colell Riera, Anna ; Morales, Albert ; García-Ruiz, Carmen ; Fernández-Checa, José C. ; Varela-Nieto, Isabel ; Pañeda, Covadonga
Issue Date15-Mar-2004
PublisherAmerican Society for Clinical Investigation
CitationJournal of Clinical Investigation 113(6): 895–904 (2004)
AbstractS-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-α. 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-α but were responsive to exogenous ASMase-induced downregulation of MAT1A. In an in vivo model of lethal hepatitis by TNF-α, 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-α–induced lethality. Thus, we have demonstrated a new role for ASMase in TNF-α–induced liver failure through downregulation of MAT1A, and maintenance of SAM may be useful in the treatment of acute and chronic liver diseases.
Publisher version (URL)http://dx.doi.org/10.1172/JCI200419852
URIhttp://hdl.handle.net/10261/5351
DOI10.1172/JCI200419852
ISSN0021-9738
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