Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice

Resistin-like molecule beta (RELM beta) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELM beta to non-alcoholic steatohepatitis (NASH) development. First, RELM beta knock-out (KO) mice were shown to be resistant to methionine-choline deficient (MCD) diet-induced NASH development. Since it was newly revealed that Kupffer cells in the liver express RELM beta and that RELM beta expression levels in the colon and the numbers of RELM beta-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELM beta-KO mice to distinguish between the contributions of RELM beta in these two organs. These experiments revealed the requirement of RELM beta in both organs for full manifestation of NASH, while deletion of each one alone attenuated the development of NASH with reduced serum lipopolysaccharide (LPS) levels. The higher proportion of lactic acid bacteria in the gut microbiota of RELM beta-KO than in that of wild-type mice may be one of the mechanisms underlying the lower serum LPS level the former. These data suggest the contribution of increases in RELM beta in the gut and Kupffer cells to NASH development, raising the possibility of RELM beta being a novel therapeutic target for NASH.