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.

非酒精性脂肪性肝病（Non-alcoholic fatty liver disease, NAFLD）现已成为全球范围内最为高发的肝脏疾病。本研究借助饮食诱导的非酒精性脂肪性肝病小鼠模型，在为期13周的喂食实验的最后5周，通过口服补充非蛋白源性氨基酸L-瓜氨酸（L-citrulline，缩写为Cit，剂量为2.5g Cit/kg体重），探究其能否缓解雌性C57Bl/6小鼠中已存在的非酒精性脂肪性肝病的进展。补充L-瓜氨酸对非酒精性脂肪性肝病进展的保护作用，与小肠组织中细菌内毒素易位增加、紧密连接蛋白丢失以及精氨酸酶活性升高的缓解相关；与此同时，小肠内的肠道菌群组成并未出现显著变化。使用精氨酸酶抑制剂nor-NOHA（剂量为0.01g/kg体重，腹腔注射）处理小鼠后，L-瓜氨酸对饮食诱导的非酒精性脂肪性肝病的保护作用被完全抵消。本研究结果表明，L-瓜氨酸对非酒精性脂肪性肝病发生与进展的保护作用，与小肠精氨酸酶活性及肠道通透性的改变密切相关。