Acidic sphingomyelinase downregulates the liver-specific methionine adenosyltransferase 1A, contributing to tumor necrosis factor-induced lethal hepatitis.
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.
Marí
Montserrat
M
Liver Unit, Institut de Malalties Digestives, Hospital Clínic i Provincial, Instituto Investigaciones Biomédicas August Pi i Sunyer, Barcelona, Spain.
Colell
Anna
A
Morales
Albert
A
Pañeda
Covadonga
C
Varela-Nieto
Isabel
I
García-Ruiz
Carmen
C
Fernández-Checa
José C
JC
D000123:Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D015536:Down-Regulation; D006505:Hepatitis / Q000188:drug therapy / Q000201:enzymology*; D051379:Mice; D018345:Mice, Knockout; D012436:S-Adenosylmethionine / Q000494:pharmacology; D013108:Sphingomyelin Phosphodiesterase / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000009:adverse effects
D000970:Antineoplastic Agents; D014409:Tumor Necrosis Factor-alpha; D012436:S-Adenosylmethionine; D000123:Acetyltransferases; C045222:methionine acetyltransferase; D013108:Sphingomyelin Phosphodiesterase