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Nutrient Physiology, Metabolism, and Nutrient-Nutrient Interactions

Impaired Sulfur-Amino Acid Metabolism and Oxidative Stress in Nonalcoholic Fatty Liver Are Alleviated by Betaine Supplementation in Rats^1,2

³ College of Pharmacy, ⁴ College of Veterinary Medicine, and ⁵ Research Institute of Pharmaceutical Sciences, Seoul National University, San 56-1 Shinrim-Dong, Kwanak-Ku, Seoul 151-742, Korea

Nonalcoholic fatty liver is involved in the development of nonalcoholic steatohepatitis and chronic liver injury. Impairment of hepatic transsulfuration reactions is suggested to be critically linked with alcoholic liver injury, but its role in nonalcoholic fatty liver remains unknown. We examined the early changes in sulfur-amino acid metabolism and their implication in nonalcoholic fatty liver disease (NAFLD). Male rats were provided with a standard liquid diet or a high-fat liquid diet (HF) for 3 wk. An additional group of rats received the HF diet supplemented with betaine (1%). HF diet intake elevated hepatic triglyceride and serum tumor necrosis factor- (TNF) concentrations. Antioxidant capacity of liver cytosol against hydroxyl and peroxyl radicals was reduced significantly. Hepatic S-adenosylmethionine (SAM) and glutathione (GSH) decreased, but hypotaurine and taurine concentrations increased. Methionine adenosyltransferase (MAT) activity, not its concentration, was depressed, whereas both activity and concentration of cysteine dioxygenase and GSH S-transferase were elevated. Betaine supplementation of the HF diet inhibited hepatic fat accumulation and serum TNF elevation. The decrease in cytosolic antioxidant capacity was also prevented. MAT activity and its concentration were induced significantly. Hepatic SAM and GSH increased and elevation of hypotaurine and taurine was depressed. The results indicate that the metabolism of S-containing substances is significantly disturbed by the HF diet, suggesting a causal role of impairment of hepatic transsulfuration reactions in NAFLD. Betaine supplementation protects the liver from nonalcoholic steatosis and oxidative stress most probably via its effects on the transsulfuration reactions.

^* To whom correspondence should be addressed. E-mail: youckim{at}snu.ac.kr.

Manuscript received 18 June 2008. Initial review completed 11 July 2008. Revision accepted 30 October 2008.

Published online 3 December 2008.