Background and aim: The liver plays a crucial role in the metabolism of asymmetric-dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide (NO) synthase. ADMA is metabolized via dimethylarginine-dimethylaminohydrolase (DDAH). This study investigated whether, in a rat model of nonalcoholic steatohepatitis (NASH), changes in serum levels of ADMA occur and the mechanisms involved. Materials and methods: Male Wistar rats underwent to NASH induced by 8 weeks of feeding with an MCD diet (methionine/choline-deficient diet). Blood samples and hepatic biopsies were collected after 1, 2, 3, 4 and 8 weeks. Serum hepatic enzymes (AST, ALT and g-GT) and ADMA were evaluated. Hepatic biopsies were used for in situ NAD(P)H autofluorescence detection and for mRNA expression of DDAH and ADMA transporters (CAT-1) by RT-PCR. Tissue DDAH activity and content of lipid peroxides, glutathione and ATP were also quantified. Results: NASH injury was confirmed by altered serum levels of hepatic enzymes. A time dependent decrease in serum ADMA levels and an increase in mRNA expression of DDAH and CAT-1 were found. The hepatic DDAH activity decrease with a concomitant increase in oxidative stress, as demonstrated by high lipid peroxide levels and low GSH content. A decrease in ATP levels and in the NAD(P)Hbound/free ratio reflecting the mitochondria alterations were detected. Conclusions: These results indicate that while an increase in DDAH mRNA was found, the oxidative stress observed can contribute to the reduction of DDAH activity. This enzyme is a cysteine hydrolase that may be inhibited by increased reactive oxygen species associated to mitochondria dysfunction. The observed decrease in serum ADMA may be due to the increase in ADMA transporter, CAT-1. These data confirm and support the crucial role of the liver in the control of ADMA levels by taking up large amounts of ADMA from the systemic circulation. (Supported by Fondazione Cariplo, grant n° 2011-0439).
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