東京大学医科学研究所

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学友会セミナー

学友会セミナー:2016年9月15日

開催日時: 2016年9月15日 18:00~19:00
開催場所: 2号館 大講義室
講師: 櫛 山 暁 史
所属: 公益財団法人 朝日生命成人病研究所・医長
演題: Linking dietary fat, microbiota, innate immunity and lifestyle-relate diseases by resistin like molecule β
概要:

Resistin like molecule  (RELM) reportedly possesses the multiple functions including local immune response and regulation of microbiota. We revealed that not only mucus secreting epithelial cells but also macrophages in the atherosclerotic tissue and Kupffer cells in the liver express RELM High fat diet or saturated FFA increases RELMβ expression in both cells. Circulating RELMβ suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet.
Both RELM expression levels in the colon and the numbers of RELM-positive Kupffer cells were markedly increased in mice liver by methionine-choline deficient diet (MCD) feeding and in human liver of the patients with NASH. Furthermore, RELM mice were highly resistant to atherosclerosis in ApoEKO mice and the MCD-induced NASH. RELM regulated the intestinal environment, such as gut permeability measured by LPS absorption and microbiota. RELM directly enhanced immune responses of the macrophages, thus RELMKO macrophages showed less lipid accumulation and lower responsibility for LPS than control macrophages. The radiation chimeras between the wild-type and RELM KO mice revealed the requirement of both non-hematopoietic and hematopoietic cell-derived RELM for full manifestation of NASH. Increased RELM in the gut might contribute to the impaired barrier function of the colon and its resultant increased LPS absorption from the gut, while Kupffer cell-derived RELM to the high responsibility for LPS-induced inflammatory response in the liver.
We hypothesize that dietary saturated fatty acids induce RELMβ expression, signaling the necessity for inflammation into the systemic macrophages including remote foam cells and Kupffer cells, leading to chronic inflammation of lifestyle-related diseases.
1. Okubo H et al. Involvement of resistin-like molecule β in the development of methionine-choline deficient diet-induced non-alcoholic steatohepatitis in mice. Sci Rep. 2016 Jan 28;6:20157. doi: 10.1038/srep20157.
2. Kushiyama A et al. Resistin-like molecule β is abundantly expressed in foam cells and is involved in atherosclerosis development. Arterioscler Thromb Vasc Biol. 2013 Aug;33(8):1986-93. doi:10.1161/ATVBAHA.113.301546.
3. Kushiyama A et al. Resistin-like molecule beta activates MAPKs, suppresses insulin signaling in hepatocytes, and induces diabetes, hyperlipidemia, and fatty liver in transgenic mice on a high fat diet. J Biol Chem. 2005 Dec 23;280(51):42016-25.

世話人: ○田中 廣壽(抗体・ワクチンセンター 免疫病治療学分野 教授)
 細野 治 (アレルギー免疫科 准教授)