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

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dc.creator Marí, Montserrat
dc.creator Colell Riera, Anna
dc.creator Morales, Albert
dc.creator García-Ruiz, Carmen
dc.creator Fernández-Checa, José C.
dc.creator Varela-Nieto, Isabel
dc.creator Pañeda, Covadonga
dc.date 2008-06-26T07:28:28Z
dc.date 2008-06-26T07:28:28Z
dc.date 2004-03-15
dc.date.accessioned 2017-01-31T01:53:02Z
dc.date.available 2017-01-31T01:53:02Z
dc.identifier Journal of Clinical Investigation 113(6): 895–904 (2004)
dc.identifier 0021-9738
dc.identifier http://hdl.handle.net/10261/5351
dc.identifier 10.1172/JCI200419852
dc.identifier.uri http://dspace.mediu.edu.my:8181/xmlui/handle/10261/5351
dc.description 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-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.
dc.description The work presented was supported in part by the Research Center for Liver and Pancreatic Diseases, P50 AA 11999; and grant 1R21 AA014135-01, funded by the US National Institute on Alcohol Abuse and Alcoholism; Plan Nacional de I+D grants SAF01-2118, SAF2002-3564, and SAF2003-04974; and Red Temática de Investigación Cooperativa G03/015 and Red de Centros C03/02, supported by Instituto de Salud Carlos III. We want to thank Susana Nuñez for expert technical assistance and genotyping of ASMase–/– mice. M. Marí and A. Morales are Ramón y Cajal investigators.
dc.description Peer reviewed
dc.format 3641378 bytes
dc.format application/pdf
dc.language eng
dc.publisher American Society for Clinical Investigation
dc.relation http://dx.doi.org/10.1172/JCI200419852
dc.rights openAccess
dc.title Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor–induced lethal hepatitis
dc.type Artículo


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