Kumazoe Motofumi, Nakamura Yuki, Yamashita Mai, Suzuki Takashi, Takamatsu Kanako, Huang Yuhui, Bae Jaehoon, Yamashita Shuya, Murata Motoki, Yamada Shuhei, Shinoda Yuki, Yamaguchi Wataru, Toyoda Yui, Tachibana Hirofumi
From the Division of Applied Biological Chemistry, Department of Bioscience and Biotechnology, Faculty of Agriculture, Kyushu University, Fukuoka 812-8581 and.
the Products Research & Development Laboratory, Asahi Soft Drinks Co., Ltd., Ibaraki 302-0106, Japan.
J Biol Chem. 2017 Mar 10;292(10):4077-4088. doi: 10.1074/jbc.M116.755959. Epub 2017 Feb 1.
Toll-like receptor 4 (TLR4) plays an essential role in innate immunity through inflammatory cytokine induction. Recent studies demonstrated that the abnormal activation of TLR4 has a pivotal role in obesity-induced inflammation, which is associated with several diseases, including hyperinsulinemia, hypertriglyceridemia, and cardiovascular disease. Here we demonstrate that (-)-epigallocatechin-3--gallate, a natural agonist of the 67-kDa laminin receptor (67LR), suppressed TLR4 expression through E3 ubiquitin-protein ring finger protein 216 (RNF216) up-regulation. Our data indicate cyclic GMP mediates 67LR agonist-dependent RNF216 up-regulation. Moreover, we show that the highly absorbent 67LR agonist (-)-epigallocatechin-3--(3--methyl)-gallate (EGCG3″Me) significantly attenuated TLR4 expression in the adipose tissue. EGCG3″Me completely inhibited the high-fat/high-sucrose (HF/HS)-induced up-regulation of tumor necrosis factor α in adipose tissue and serum monocyte chemoattractant protein-1 increase. Furthermore, this agonist intake prevented HF/HS-induced hyperinsulinemia and hypertriglyceridemia. Taken together, 67LR presents an attractive target for the relief of obesity-induced inflammation.
Toll样受体4（TLR4）通过诱导炎性细胞因子在先天免疫中发挥重要作用。最近的研究表明，TLR4的异常激活在肥胖诱导的炎症中起关键作用，而肥胖诱导的炎症与包括高胰岛素血症、高甘油三酯血症和心血管疾病在内的多种疾病相关。在此，我们证明67 kDa层粘连蛋白受体（67LR）的天然激动剂（-）-表没食子儿茶素-3-没食子酸酯通过上调E3泛素-蛋白环指蛋白216（RNF216）来抑制TLR4表达。我们的数据表明环鸟苷酸介导67LR激动剂依赖性RNF216上调。此外，我们表明高吸收性的67LR激动剂（-）-表没食子儿茶素-3-（3-甲基）-没食子酸酯（EGCG3″Me）显著减弱脂肪组织中TLR4的表达。EGCG3″Me完全抑制高脂肪/高蔗糖（HF/HS）诱导的脂肪组织中肿瘤坏死因子α上调以及血清单核细胞趋化蛋白-1增加。此外，摄入这种激动剂可预防HF/HS诱导的高胰岛素血症和高甘油三酯血症。综上所述，67LR是缓解肥胖诱导炎症的一个有吸引力的靶点。
