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-specificMAT1A gene results in liver neoplasia and sensitivity to oxidant injury.Here we show that acidic sphingomyelinase (ASMase) mediates the downregulation of MAT1A by TNF- .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- but were responsive to exogenous ASMase-induced downregulation of MAT1A.In an in vivo model of lethal hepatitis by TNF- , 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- -induced lethality.Thus, we have demonstrated a new role for ASMase in TNF- -induced liver failure through downregulation of MAT1A, and maintenance of SAM may be useful in the treatment of acute and chronic liver diseases.Nonstandard abbreviations used: acidic sphingomyelinase (ASMase); alanine aminotransferase (ALT); Bacillus cereus sphingomyelinase (bNSMase); D-(+)-galactosamine (Gal); D-threo-1-phenyl-2-decanoylamino-3-morpholino-propanol HCl (D-threo-PDMP); ganglioside GD3 (GD3); ganglioside GM3 (GM3); glucosylceramide synthase (GCS); -glutamylcysteine synthetase (-GCS); glutathione (GSH); human placenta sphingomyelinase (hASMase); L-buthionine sulfoximine (BSO); liver-specific methionine adenosyltransferase (MAT1A); mannose 6-phosphate (M 6-P); methionine adenosyltransferase (MAT); N-acetylcysteine (NAC); neutral sphingomyelinase (NSMase); S-adenosyl-L-homocysteine (SAH); S-adenosyl-L-methionine (SAM); sphingomyelinase (SMase).