Cyanidin, a natural flavonoid, is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes
Cyanidin, a natural flavonoid, is an agonistic ligand for liver X receptor alpha and beta and reduces cellular lipid accumulation in macrophages and hepatocytes
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DOI：
10.1016/j.bmcl.2013.05.030
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发表时间：
2013-07-15
影响因子：
2.7
通讯作者：
Lee, Sung-Joon
中科院分区：
文献类型：
--
作者：
Jia, Yaoyao;Hoang, Minh Hien;Lee, Sung-Joon
矢车菊素是一种富含于水果和蔬菜中的天然类黄酮，已知其调节细胞脂质代谢;然而，其潜在的作用机制和蛋白质靶点仍然未知。在这里，花青素对肝脏X受体（LXRs）的配体结合活性进行了研究，利用表面等离子体共振和时间分辨荧光能量转移（TR-FRET）分析。LXR是细胞核受体，在调节细胞脂质和葡萄糖代谢中作为关键转录因子发挥作用。这包括刺激高密度脂蛋白合成和激活胆固醇逆向转运。目前的研究结果表明，矢车菊素诱导LXR的反式激活，并直接结合到LXR α和LXR β的配体结合域，解离常数分别为2.2和73.2 μ M。无细胞的FRET分析表明，矢车菊素诱导的招募共激活肽LXRa和LXRb的EC 50分别为3.5 μ M和125.2 μ M。此外，胞内胆固醇和甘油三酯（TG）浓度降低后，花青素刺激巨噬细胞。在培养的肝细胞中，矢车菊素轻度诱导SREBP 1c基因表达，但轻微影响细胞TG浓度，以及减少细胞胆固醇积累，从而激活胆固醇逆向转运基因的表达。两个矢车菊素代谢产物，原儿茶酸和间苯三甲醛，没有直接绑定或激活LXR。这些结果表明矢车菊素是LXR α和LXR β的直接配体，表明矢车菊素可能至少部分通过调节细胞LXR活性来起作用。(C)2013爱思唯尔有限公司保留所有权利。
Cyanidin, a natural flavonoid abundant in fruits and vegetables, is known to regulate cellular lipid metabolism; however, its underlying mechanism of action and protein targets remain unknown. Here, the ligand binding activity of cyanidin on liver X receptors (LXRs) was investigated utilizing surface plasmon resonance and time-resolved fluorescence energy transfer (TR-FRET) analyses. LXRs are nuclear receptors which function as critical transcription factors in the regulation of cellular lipid and glucose metabolism. This includes the stimulation of high-density-lipoprotein synthesis and activation of reverse cholesterol transport. The present findings show that cyanidin induces the transactivation of LXRs and binds directly to the ligand-binding domain of both LXR alpha and LXR beta with dissociation constants of 2.2 and 73.2 mu M, respectively. Cell-free FRET analysis demonstrated that cyanidin induces the recruitment of co-activator peptide for LXRa and LXRb with EC50 of 3.5 mu M and 125.2 mu M, respectively. In addition, intracellular cholesterol and triglyceride (TG) concentrations were reduced in macrophages following cyanidin stimulation. In cultured hepatocytes, cyanidin mildly induced SREBP1c gene expression but marginally affected cellular TG concentrations as well as reduced cellular cholesterol accumulations which activated the expression of genes for reverse cholesterol transport. Two cyanidin metabolites, procatechic acid and phloroglucinaldehyde, did not directly bind or activate LXRs. These results demonstrate that cyanidin is a direct ligand for both LXR alpha and LXR beta, suggesting that cyanidin may operate, at least in part, through modulation of cellular LXR activity. (C) 2013 Elsevier Ltd. All rights reserved.