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

Hirofumi Okubo,Hideaki Kamata,Tomoichiro Asano,Naoyuki Taki,Akifumi Kushiyama,Masaki Iizuka,Midori Fujishiro,Akiko Nagamachi,Takashi Asahara,Hideki Katagiri,Toshiaki Fukushima,Jeffery Encinas,Fusanori Nishimura,Hideyuki Sakoda,Yasuto Yoshida,Yusuke Nakatsu,Osamu Chonan,Toshiya Inaba

doi:10.1038/srep20157

Abstract

Resistin-like molecule β (RELMβ) reportedly has multiple functions including local immune responses in the gut. In this study, we investigated the possible contribution of RELMβ to non-alcoholic steatohepatitis (NASH) development. First, RELMβ 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 RELMβ and that RELMβ expression levels in the colon and the numbers of RELMβ-positive Kupffer cells were both increased in this model, we carried out further experiments using radiation chimeras between wild-type and RELMβ-KO mice to distinguish between the contributions of RELMβ in these two organs. These experiments revealed the requirement of RELMβ 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 RELMβ-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 RELMβ in the gut and Kupffer cells to NASH development, raising the possibility of RELMβ being a novel therapeutic target for NASH.

Highlights

Stress, inflammatory cytokines and endotoxins that are considered to play important roles as the predominant causes of liver neutrophil infiltration[1], and the resultant liver damage[2,3]
We previously reported that transgenic mice overexpressing RELMβ showed significant insulin resistance with fatty liver when fed a high fat diet[23], findings which already suggested the involvement of RELMβ in the pathogenesis of insulin resistance
In the present study designed to investigate the contribution of RELMβ to the pathogenesis of non-alcoholic steatohepatitis (NASH), we adopted the methionine-choline deficient (MCD) diet-induced NASH model which does not show either obesity or insulin resistance in association with NASH

Summary

Introduction

Stress, inflammatory cytokines and endotoxins that are considered to play important roles as the predominant causes of liver neutrophil infiltration[1], and the resultant liver damage[2,3]. Serum lipopolysaccharide (LPS) elevation appears to function as a trigger of hepatic inflammation, and its continuous infusion reportedly induces hepatosteatosis in mice, suggesting the importance of serum LPS in the pathogenesis of NASH. RELM β is a protein homologous to resistin, initially identified as a factor secreted by mouse adipocytes which causes insulin resistance[7]. Associations of resistin or RELMβ with several pathological conditions, including insulin resistance[15], coronary artery disease[16], congestive heart failure[17] and intestinal inflammation[18,19,20,21,22], have been suggested. To distinguish the roles of RELMβ secreted from the gut versus that from Kupffer cells, radiation chimeras between RELMβ -KO and wild-type mice were prepared. This study provides the first evidence of the critical role of RELMβ in NASH development, and raises the possibility of RELMβ being a target for novel NASH therapies

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Conclusion