Glutathione‐enhancing agents protect against steatohepatitis in a dietary model

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Abstract
Nonalcoholic fatty liver (NAFL) and steatohepatitis (NASH) may accompany obesity, diabetes, parenteral nutrition, jejeuno‐ileal bypass, and chronic inflammatory bowel disease. Currently there is no FDA approved and effective therapy available. We investigated the potential efficacy of those agents that stimulate glutathione (GSH) biosynthesis on the development of experimental steatohepatitis. Rats fed (ad libitum) amino acid based methionine‐choline deficient (MCD) diet were further gavaged with (1) vehicle (MCD), (2)S‐adenosylmethionine (SAMe), or (3) 2(RS)‐n‐propylthiazolidine‐4(R)‐carboxylic acid (PTCA). Results: MCD diet significantly reduced hematocrit, and this abnormality improved in the treated groups (p< 0.01). Serum transaminases were considerably elevated (AST: 5.8‐fold; ALT: 3.22‐fold) in MCD rats. However, administration of GSH‐enhancing agents significantly suppressed these abnormal enzyme activities. MCD rats developed severe liver pathology manifested by fatty degeneration, inflammation, and necrosis, which significantly improved with therapy. Blood levels of GSH were significantly depleted in MCD rats but normalized in the treated groups. Finally, RT‐PCR measurements showed a significant upregulation of genes involved in tissue remodeling and fibrosis (matrix metalloproteinases, collagen‐α1), suppressor of cytokines signaling1, and the inflammatory cytokines (IL‐1β, IL‐6, TNF‐α, and TGF‐β) in the livers of rats fed MCD. GSH‐enhancing therapies significantly attenuated the expression of deleterious proinflammatory and fibrogenic genes in this dietary model. This is the first report that oral administration of SAMe and PTCA provide protection against liver injury in this model and suggests therapeutic applications of these compounds in NASH patients. © 2006 Wiley Periodicals, Inc. J Biochem Mol Toxicol 20:39–47, 2006; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20109