Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 113, Issue 6, Pages 895-904Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200419852
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Funding
- NIAAA NIH HHS [P50 AA 11999, 1R21 AA014135-01, R21 AA014135, P50 AA011999] Funding Source: Medline
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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 NUT 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 MATIA. 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.
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