Citrulline attenuates the development of non-alcoholic steatohepatitis: Role of intestinal arginase

Non-alcoholic fatty liver disease (NAFLD) is by now the most prevalent liver disease in the world. Here, using a mouse model of diet-induced NAFLD, we assessed if oral supplementation of the non-proteogenic amino acid L-citrulline (Cit, 2.5g Cit/kg BW) for the last 5 weeks of the 13 week feeding experiment attenuated the progression of a pre-existing NAFLD in female C57Bl/6 mice. The protective effects of supplementing Cit on the progression of NAFLD were associated with an attenuation of the increased translocation of bacterial endotoxin and the loss of tight junction proteins as well as arginase activity in small intestinal tissue while no marked changes in intestinal microbiota composition were prevalent in small intestine. Treatment of mice with the arginase inhibitor nor-NOHA (0.01g/kg BW i.p.) abolished the protective effects of Cit on diet-induced NAFLD. Our results suggest that the protective effects of Cit on the development and progression of NAFLD are related to alterations of intestinal arginase activity and permeability.