Department of Medicine, University of Tennessee Health Science Center, 19 S Manassas St., Memphis, TN, 38163, USA.
UT/ORNL Center for Molecular Biophysics, Oak Ridge, TN, 37830, USA.
Mol Nutr Food Res. 2018 Apr;62(8):e1700770. doi: 10.1002/mnfr.201700770. Epub 2018 Apr 14.
The molecular mechanisms whereby gallates in green tea exert metabolic effects are poorly understood.
We found that GPRC6A, a multi-ligand-sensing G-protein-coupled receptor that regulates energy metabolism, sex hormone production, and prostate cancer progression, is a target for gallates. Sodium gallate (SG), gallic acid (GA) > ethyl gallate (EG) > octyl gallate (OG) dose dependently activated ERK in HEK-293 cells transfected with GPRC6A but not in non-transfected controls. SG also stimulated insulin secretion in β-cells isolated from wild-type mice similar to the endogenous GPRC6A ligands, osteocalcin (Ocn) and testosterone (T). Side-chain additions to create OG resulted in loss of GPRC6A agonist activity. Another component of green tea, epigallocatechin 3-gallate (EGCG), dose-dependently inhibited Ocn activation of GPRC6A in HEK-293 cells transfected with GPRC6A and blocked the effect of Ocn in stimulating glucose production in CH10T1/2 cells. Using structural models of the venus fly trap (VFT) and 7-transmembrane (7-TM) domains of GPRC6A, calculations suggest that l-amino acids and GA bind to the VFT, whereas EGCG is calculated to bind to sites in both the VFT and 7-TM.
GA and EGCG have offsetting agonist and antagonist effects on GPRC6A that may account for the variable metabolic effect of green tea consumption.
绿茶中的没食子酸酯发挥代谢作用的分子机制还不太清楚。
我们发现，GPRC6A 是一种多配体感应 G 蛋白偶联受体，可调节能量代谢、性激素产生和前列腺癌进展，是没食子酸酯的靶点。焦谷氨酸钠 (SG)、没食子酸 (GA) > 乙基没食子酸酯 (EG) > 辛基没食子酸酯 (OG) 剂量依赖性地激活转染 GPRC6A 的 HEK-293 细胞中的 ERK，但在未转染对照中则没有。SG 还刺激来自野生型小鼠的β细胞中的胰岛素分泌，类似于内源性 GPRC6A 配体骨钙素 (Ocn) 和睾酮 (T)。创建 OG 的侧链添加导致失去 GPRC6A 激动剂活性。绿茶的另一种成分，表没食子儿茶素 3-没食子酸酯 (EGCG)，剂量依赖性地抑制转染 GPRC6A 的 HEK-293 细胞中 Ocn 激活 GPRC6A，并阻断 Ocn 刺激 CH10T1/2 细胞葡萄糖产生的作用。使用维纳斯捕蝇草 (VFT) 和 GPRC6A 的 7-跨膜 (7-TM) 结构模型，计算表明 l-氨基酸和 GA 结合到 VFT，而 EGCG 计算结果表明结合到 VFT 和 7-TM 中的位点。
GA 和 EGCG 对 GPRC6A 具有拮抗和激动作用，这可能解释了绿茶消费对代谢的不同影响。
