Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.
Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice.
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DOI：
10.1038/srep20157
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发表时间：
2016-01-28
影响因子：
4.6
通讯作者：
Asano T
中科院分区：
文献类型：
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作者：
Okubo H;Kushiyama A;Sakoda H;Nakatsu Y;Iizuka M;Taki N;Fujishiro M;Fukushima T;Kamata H;Nagamachi A;Inaba T;Nishimura F;Katagiri H;Asahara T;Yoshida Y;Chonan O;Encinas J;Asano T
据报道，抵抗素样分子β（RELMβ）具有多种功能，包括肠道局部免疫应答。在本研究中，我们研究了RELMβ对非酒精性脂肪性肝炎（NASH）发展的可能贡献。首先，RELMβ基因敲除（KO）小鼠对蛋氨酸胆碱缺乏（MCD）饮食诱导的NASH发展具有抗性。由于新发现肝脏中的库普弗细胞表达RELMβ，并且在该模型中结肠中的RELMβ表达水平和RELMβ阳性库普弗细胞的数量均增加，因此我们使用野生型和RELMβ-KO小鼠之间的辐射嵌合体进行了进一步的实验，以区分RELMβ在这两个器官中的作用。这些实验揭示了NASH的完全表现需要两种器官中的RELMβ，而单独缺失每一种都会减弱NASH的发展，同时降低血清脂多糖（LPS）水平。乳酸菌在RELMβ-KO小鼠肠道菌群中的比例高于野生型小鼠，这可能是前者血清LPS水平较低的机制之一。这些数据表明肠道和库普弗细胞中RELMβ的增加对NASH发展的贡献，提高了RELMβ成为NASH新治疗靶点的可能性。
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.