Stefela Alzbeta, Kaspar Miroslav, Drastik Martin, Kronenberger Thales, Micuda Stanislav, Dracinsky Martin, Klepetarova Blanka, Kudova Eva, Pavek Petr
Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czechia.
Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czechia.
Front Pharmacol. 2021 Aug 13;12:713149. doi: 10.3389/fphar.2021.713149. eCollection 2021.
Bile acids (BAs) are key signaling steroidal molecules that regulate glucose, lipid, and energy homeostasis via interactions with the farnesoid X receptor (FXR) and G-protein bile acid receptor 1 (GPBAR1). Extensive medicinal chemistry modifications of the BA scaffold led to the discovery of potent selective or dual FXR and GPBAR1 agonists. Herein, we discovered 7-ethylidene-lithocholic acid (7-ELCA) as a novel combined FXR antagonist/GPBAR1 agonist (IC = 15 μM/EC = 26 nM) with no off-target activation in a library of 7-alkyl substituted derivatives of BAs. 7-ELCA significantly suppressed the effect of the FXR agonist obeticholic acid in BSEP and SHP regulation in human hepatocytes. Importantly, 7-ELCA significantly stimulated the production of glucagon-like peptide-1 (GLP-1), an incretin with insulinotropic effect in postprandial glucose utilization, in intestinal enteroendocrine cells. We can suggest that 7-ELCA may be a prospective approach to the treatment of type II diabetes as the dual modulation of GPBAR1 and FXR has been supposed to be effective in the synergistic regulation of glucose homeostasis in the intestine.
胆汁酸（BAs）是关键的信号甾体分子，通过与法尼醇X受体（FXR）和G蛋白胆汁酸受体1（GPBAR1）相互作用来调节葡萄糖、脂质和能量稳态。对BA支架进行广泛的药物化学修饰，导致发现了强效的选择性或双重FXR和GPBAR1激动剂。在此，我们发现7-亚乙基石胆酸（7-ELCA）是一种新型的FXR拮抗剂/GPBAR1激动剂组合（IC = 15 μM/EC = 26 nM），在BA的7-烷基取代衍生物库中无脱靶激活。7-ELCA显著抑制了FXR激动剂奥贝胆酸对人肝细胞中BSEP和SHP调节的作用。重要的是，7-ELCA显著刺激了胰高血糖素样肽-1（GLP-1）的产生，GLP-1是一种在餐后葡萄糖利用中具有促胰岛素作用的肠促胰岛素，在肠道肠内分泌细胞中发挥作用。我们可以认为，7-ELCA可能是治疗II型糖尿病的一种有前景的方法，因为对GPBAR1和FXR的双重调节被认为在协同调节肠道葡萄糖稳态方面是有效的。
