TMPA, a Nur77 antagonist, prevents the binding of Nur77 and LKB1 as well as stimulates LKB1 transport to the cytosol and phosphorylation [1]. The binding of TMPA to Nur77 decreases the stability of Nur77-LKB1 complex by inducing an open-close motion of Nur77 and thereby facilitates the solvation of the interface region[2]. TMPA has been widely used in diabetic mouse models to regulate blood glucose levels[3].
In vitro, TMPA treatment at 10μM for 1 hour increased the phosphorylation of AMPK in hepatic L02 cells [4]. Treatment of mouse bone marrow-derived mast cells (BMMCs) with 10μM TMPA for 6 hours increased phosphorylation of LKB1 and AMPK and concomitantly reduced IgE/Ag-induced degranulation and eicosanoid production, which inhibited FcεRI-mediated mast cell signaling[5]. Treatment with 10μM TMPA for 18h significantly increased TNFα-induced IL-6 production in HeLa cells[6]. Pretreatment of HepG2 cells with 10μM TMPA for 6 hours reduced lipid accumulation after free fatty acid (FFA) stimulation[7].
In vivo, Intraperitoneal injection of TMPA (50mg/kg/day) once daily for 19 days significantly reduced insulin levels, lowered blood glucose, and improved glucose tolerance in diabetic mice[8].
References:
[1] Wu L, Chen L. Characteristics of Nur77 and its ligands as potential anticancer compounds[J]. Molecular medicine reports, 2018, 18(6): 4793-4801.
[2] Rungsung I, Rajagopalan M, Ramaswamy A. Molecular dynamics study of TMPA mediated dissociation of Nur77-LKB1 complex[J]. Computational Biology and Chemistry, 2018, 76: 67-78.
[3] Safe S. Natural products and synthetic analogs as selective orphan nuclear receptor 4A (NR4A) modulators[J]. Histology and histopathology, 2023, 39(5): 543.
[4] Li L, Liu Y, Chen H, et al. Impeding the interaction between Nur77 and p38 reduces LPS-induced inflammation[J]. Nature chemical biology, 2015, 11(5): 339-346.
[5] Jin F, Li X, Deng Y, et al. The orphan nuclear receptor NR4A1 promotes FcεRI‐stimulated mast cell activation and anaphylaxis by counteracting the inhibitory LKB1/AMPK axis[J]. Allergy, 2019, 74(6): 1145-1156.
[6] Huang B, Pei H Z, Chang H W, et al. The E3 ubiquitin ligase Trim13 regulates Nur77 stability via casein kinase 2α[J]. Scientific reports, 2018, 8(1): 13895.
[7] Wang X, Li G, Guo C, et al. Ethyl 2-[2, 3, 4-Trimethoxy-6-(1-Octanoyl) Phenyl] acetate (Tmpa) ameliorates lipid accumulation by disturbing the combination of Lkb1 with Nur77 and activating the ampk pathway in Hepg2 cells and mice primary hepatocytes[J]. Diabetes, Metabolic Syndrome and Obesity, 2021: 4165-4177.
[8] Zhan Y, Chen Y, Zhang Q, et al. The orphan nuclear receptor Nur77 regulates LKB1 localization and activates AMPK[J]. Nature chemical biology, 2012, 8(11): 897-904.
TMPA是一种Nur77拮抗剂，可阻止Nur77与LKB1的结合，并刺激LKB1向胞质转运及磷酸化[1]。TMPA通过诱导Nur77的开放-闭合运动降低Nur77-LKB1复合物的稳定性，从而促进界面区域的溶剂[2]。TMPA已广泛应用于糖尿病小鼠模型中调节血糖水平[3]。
在体外，10μM的TMPA处理肝L02细胞1小时可增加AMPK磷酸化[4]。10μM的TMPA处理小鼠骨髓来源肥大细胞（BMMCs）6小时能提高LKB1和AMPK磷酸化水平，同时减少IgE/抗原诱导的脱颗粒和类二十烷酸产生，并抑制FcεRI介导的肥大细胞信号传导[5]。10μM的TMPA处理HeLa细胞18小时可显著增强TNFα诱导的IL-6产生[6]。10μM的TMPA预处理HepG2细胞6小时能减少游离脂肪酸（FFA）刺激后的脂质积累[7]。
在体内，糖尿病小鼠每日腹腔注射TMPA（50mg/kg/day；持续19天）可显著降低胰岛素水平、血糖并改善葡萄糖耐量[8]。