期刊
MOLECULAR PHARMACOLOGY
卷 84, 期 5, 页码 710-725出版社
AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS
DOI: 10.1124/mol.113.087783
关键词
-
资金
- Biotechnology and Biosciences Research Council [BB/K019864/1, BB/K019856/1]
- MRC Toxicology Unit
- Danish Council for Strategic Research [11-116196]
- Canadian Institutes of Health Research
- BBSRC [BB/K019864/1, BB/K019856/1] Funding Source: UKRI
- MRC [MC_UP_A600_1110, G1100712] Funding Source: UKRI
- Biotechnology and Biological Sciences Research Council [1062317, 1653478, BB/K019864/1, BB/K019856/1] Funding Source: researchfish
- Medical Research Council [G1100712, MC_UP_A600_1110] Funding Source: researchfish
TUG-891 [3-(4-((4-fluoro-4'-methyl-[1,1'-biphenyl]-2-yl) methoxy) phenyl) propanoic acid] was recently described as a potent and selective agonist for the long chain free fatty acid (LCFA) receptor 4 (FFA4; previously G protein-coupled receptor 120, or GPR120). Herein, we have used TUG-891 to further define the function of FFA4 and used this compound in proof of principle studies to indicate the therapeutic potential of this receptor. TUG-891 displayed similar signaling properties to the LCFA alpha-linolenic acid at human FFA4 across various assay end points, including stimulation of Ca2+ mobilization, beta-arrestin-1 and beta-arrestin-2 recruitment, and extracellular signal-regulated kinase phosphorylation. Activation of human FFA4 by TUG-891 also resulted in rapid phosphorylation and internalization of the receptor. While these latter events were associated with desensitization of the FFA4 signaling response, removal of TUG-891 allowed both rapid recycling of FFA4 back to the cell surface and resensitization of the FFA4 Ca2+ signaling response. TUG-891 was also a potent agonist of mouse FFA4, but it showed only limited selectivity over mouse FFA1, complicating its use in vivo in this species. Pharmacologic dissection of responses to TUG-891 in model murine cell systems indicated that activation of FFA4 was able to mimic many potentially beneficial therapeutic properties previously reported for LCFAs, including stimulating glucagon-like peptide-1 secretion from enteroendocrine cells, enhancing glucose uptake in 3T3-L1 adipocytes, and inhibiting release of proinflammatory mediators from RAW264.7 macrophages, which suggests promise for FFA4 as a therapeutic target for type 2 diabetes and obesity. Together, these results demonstrate both potential but also significant challenges that still need to be overcome to therapeutically target FFA4.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据