Linking dietary fat, microbiota, innate immunity and lifestyle-relate diseases by resistin like molecule β
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 RELMKO 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.
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