S-Adenosylmethionine, cytokines, and alcoholic liver disease.
Hepatic deficiency of S-adenosylmethionine (AdoMet) is a critical acquired metabolic abnormality in alcoholic liver disease (ALD) and in many experimental models of hepatotoxicity. Subnormal AdoMet, elevated serum tumor necrosis factor (TNF), and endotoxemia (LPS) are hallmarks of ALD and experimental liver injury. AdoMet deficiency is attributed to its subnormal synthesis, but mechanisms for increased TNF are not known. AdoMet deficiency may affect the critical balance of proinflammatory (e.g., TNF) and antiinflammatory [e.g., interleukin (IL)-10] cytokines. Rats maintained on a choline-deficient diet with limited amounts of methionine (MCD diet) developed AdoMet deficiency. When challenged with LPS, rats fed MCD diet had significantly increased serum TNF levels and worse liver injury compared with findings for controls. Exogenous AdoMet attenuated liver injury and serum TNF levels. Results of in vitro studies with the use of RAW 264.7 cells demonstrated that exogenous AdoMet supplementation lowered LPS-induced TNF formation in a dose-dependent manner, and AdoMet deficiency enhanced TNF secretion and TNF gene expression. AdoMet also dose-dependently decreased LPS-stimulated TNF production from monocytes obtained from patients with alcoholic hepatitis. Finally, AdoMet supplementation stimulated production of the antiinflammatory cytokine IL-10. Interleukin-10 plays a critical role in the modulation of TNF production, and IL-10 may inhibit hepatic fibrosis. This article will review (1) the role of AdoMet in ALD/liver injury, (2) the role of TNF/proinflammatory cytokines in ALD, (3) potential roles of AdoMet in TNF/proinflammatory cytokine regulation in ALD, and (4) conclusions and future directions.
McClain
Craig J
CJ
Department of Medicine, University of Louisville Medical Center, KY 40292, USA. craig.mcclain@louisville.edu
Hill
Daniell B
DB
Song
Zhenyuan
Z
Chawla
Rajender
R
Watson
Walter H
WH
Chen
Theresa
T
Barve
Shirish
S
D000818:Animals; D016207:Cytokines / Q000378:metabolism*; D006801:Humans; D008108:Liver Diseases, Alcoholic / Q000188:drug therapy / Q000378:metabolism*; D012436:S-Adenosylmethionine / Q000378:metabolism* / Q000627:therapeutic use
D016207:Cytokines; D012436:S-Adenosylmethionine