小柯机器人

中国药科大学李萍、杨华和郑祖国研究组合作发现一种有效的DGKQ变构激活剂，通过sn-1,2-二酰基甘油(sn-1,2-DAG)- 蛋白激酶Cε (PKCε)信号轴改善肥胖诱导的胰岛素抵抗。相关论文于2022年12月15日发表于国际顶尖学术期刊《细胞—代谢》杂志上。

他们筛选并鉴定了植物化学物质白术内酯II (AT II)，它可以降低肝脏sn-1, -DAG水平，抑制PKCε活性，并改善肥胖诱导的高脂血症、肝骨增生和胰岛素抵抗。此外，利用ABPP策略，确定二酰基甘油激酶家族成员DGKQ是AT II的直接靶点。AT II可能作用于DGKQ的CRD和PH结构域的一个新的药物结合口袋，从而变构调节其激酶活性。此外，AT II还通过激活脂肪组织中的DGKQ-AMPK-PGC1α-UCP-1信号通路来加快体重下降。这些研究结果表明，AT II是一种很有前景的改善肥胖诱导的胰岛素抵抗的先导化合物

此外，sn-1,2-DAG介导的PKCε激活是导致肥胖相关脂代谢紊乱的关键途径，该紊乱可诱导肝脏胰岛素抵抗和2型糖尿病。以前没有关于小分子通过这一途径改善这些疾病的报道。

附：英文原文

Title: Discovery of a potent allosteric activator of DGKQ that ameliorates obesity-induced insulin resistance via the sn-1,2-DAG-PKCε signaling axis

Author: Zu-Guo Zheng, Yin-Yue Xu, Wen-Ping Liu, Yang Zhang, Chong Zhang, Han-Ling Liu, Xiao-Yu Zhang, Run-Zhou Liu, Yi-Ping Zhang, Meng-Ying Shi, Hua Yang, Ping Li

Issue&Volume: 2022-12-15

Abstract: sn-1,2-diacylglycerol (sn-1,2-DAG)-mediated activation of protein kinase Cε (PKCε)is a key pathway that is responsible for obesity-related lipid metabolism disorders,which induces hepatic insulin resistance and type 2 diabetes. No small molecules havebeen previously reported to ameliorate these diseases through this pathway. Here,we screened and identified the phytochemical atractylenolide II (AT II) that reducesthe hepatic sn-1,2-DAG levels, deactivates PKCε activity, and improves obesity-inducedhyperlipidemia, hepatosteatosis, and insulin resistance. Furthermore, using the ABPPstrategy, the diacylglycerol kinase family member DGKQ was identified as a directtarget of AT II. AT II may act on a novel drug-binding pocket in the CRD and PH domainsof DGKQ to thereby allosterically regulate its kinase activity. Moreover, AT II alsoincreases weight loss by activating DGKQ-AMPK-PGC1α-UCP-1 signaling in adipose tissue.These findings suggest that AT II is a promising lead compound to improve obesity-inducedinsulin resistance.

DOI: 10.1016/j.cmet.2022.11.012

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00503-4

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