S-adenosylmethionine deficiency and TNF-alpha in lipopolysaccharide-induced hepatic injury.
S-adenosylmethionine (Adomet) is a substrate for de novo synthesis of choline. Adomet deficiency occurs in certain types of liver injury, and the injury is attenuated by exogenous Adomet. Tumor necrosis factor-alpha (TNF-alpha) is also a mediator of these models of hepatotoxicity. We investigated the role of Adomet in lipopolysaccharide (LPS)-induced liver injury in rats made deficient in both Adomet and choline. Rats were maintained on either a methionine-restricted and choline-deficient (MCD) diet or a diet containing sufficient amounts of all nutrients [methionine and choline sufficient (MCS)] and then administered either LPS or saline. MCS-LPS rats had normal liver histology and no change in serum transaminases compared with the MCS-saline control group. MCD-saline rats had hepatosteatosis but no necrosis, and a five- to sevenfold increase in transaminases vs. the MCS-saline group. MCD-LPS rats additionally had hepatonecrosis and a 30- to 50-fold increase in transaminases. Exogenous Adomet administration to MCD-LPS rats corrected the hepatic deficiency of Adomet but not of choline, prevented necrosis but not steatosis, and attenuated transaminases. Serum TNF-alpha was sixfold higher in MCD rats even without LPS challenge and 300-fold higher with LPS challenge. Exogenous Adomet attenuated increased serum TNF-alpha in MCD-LPS rats.
Chawla
R K
RK
Department of Internal Medicine, College of Medicine, University of Kentucky, Lexington, Kentucky 40536, USA.
Watson
W H
WH
Eastin
C E
CE
Lee
E Y
EY
Schmidt
J
J
McClain
C J
CJ
D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002796:Choline Deficiency / Q000473:pathology / Q000503:physiopathology*; D005978:Glutathione / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity*; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008715:Methionine / Q000172:deficiency; D051381:Rats; D017207:Rats, Sprague-Dawley; D012436:S-Adenosylmethionine / Q000172:deficiency* / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
D008070:Lipopolysaccharides; D014409:Tumor Necrosis Factor-alpha; D012436:S-Adenosylmethionine; D008715:Methionine; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D005978:Glutathione