Innovative targets involved in the progression of NASH: Asymmetric-dymethylarginine (ADMA) and its cationic transporters

Abstract

Background: The methionine choline-deficient (MCD) diet results in liver injury similar to humannonalcoholic steatohepatitis (NASH). Recent data demonstrated that after methionine administration an increase in plasma asymmetric-dimethylarginine (ADMA), an inhibitor of nitric oxide synthase, and a decrease in hepatic dimethylarginine-dimethylaminohydrolase (DDAH-1), enzyme involved in ADMA metabolism, occur. Aim: Using an experimental model of NASH induced by MCD diet, this study investigated whether changes in serum levels of ADMA and tissue content of DDAH-1 occur [Kusku-Kiraz Z., Genc S., Bekpinar S., et al. Circulating levels of apelin, glucagon-like peptide and visfatin in hypercholesterolemic–hyperhomocysteinemic guinea-pigs: their relation with NO metabolism. Molecular and Cellular Biochemistry 2015;400:69–75;Magne J., Huneau J.-F., Borderie D., Mathe V., Bos C., Mariotti F. Plasma asymmetric and symmetric dimethylarginine in a rat model of endothelial dysfunction induced by acute hyperhomocysteinemia. Amino Acids 2015, http://dx.doi.org/10.1007/s00726-015-1959-4]. Materials and methods: Male Wistar rats underwent to NASH induced by 8 weeks of feeding with MCD diet. Serum and hepatic biopsies at 2, 4 and 8 weeks were used: serum enzymes (AST, ALT) and ADMA were evaluated. Hepatic biopsies were used for the analysis of mRNA expression of DDAH-1 and ADMA transporters (CAT-1, CAT-2A and CAT-2B). Tissue total lipids, lipid peroxides (TBARS), glutathione and DDAH activity were also quantified. Results: As expected, an increase in serum AST and ALT and in hepatic total lipids were detected in MCD animals. A time-dependent decrease in serum ADMA and increase in mRNA expression of DDAH-1 were found in MCD group. Higher mRNA expression of CAT-1, lower mRNA expression of CAT-2A and no changes in CAT-2B were found after 8 weeks using MCD diet. The hepatic DDAH activity decreased with a concomitant increase in oxidative stress, as demonstrated by high TBARS levels and low glutathione content. Conclusions: A decrease in serum ADMA levels and an increase in DDAH-1mRNA found inMCD rats were associated with a reduction in DDAH activity due to the marked oxidative stress observed. Changes in ADMA levels and its transporters represent innovative factors involved in the onset and the progression of hepatic alteration correlated with MCD-diet-induced NASH. Funding: Supported by Fondazione Cariplo, grant n◦ 2011-0439.