Abstract
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 (IC50 = 15 μM/EC50 = 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.
Highlights
Bile acids (BAs) are amphipathic steroidal molecules that facilitate the absorption of lipids, but they are important signaling agents acting as ligands of the nuclear farnesoid X receptor (FXR) and the membrane G-protein coupled bile acid receptor 1 (GPBAR1, known as Takeda G protein-coupled receptor 5, TGR5) (Donkers et al, 2019; Keitel et al, 2019; Kecman et al, 2020)
The regioselectivity of the oxidation towards the C-7 substituent is given by the different reactivity of C-3 equatorial and C-7 axial hydroxy groups, which has been described in the literature (Haslewood, 1942; Fieser and Rajagopalan, 1949; Fieser and Rajagopalan, 1950)
We introduced 7-ELCA ((E)-3α-hydroxy-7-ethylidene-5β-cholan-24-oic acid) as the first steroid compound endowed with unique and potent mixed FXR antagonistic and GPBAR1 agonistic activities
Summary
Bile acids (BAs) are amphipathic steroidal molecules that facilitate the absorption of lipids, but they are important signaling agents acting as ligands of the nuclear farnesoid X receptor (FXR) and the membrane G-protein coupled bile acid receptor 1 (GPBAR1, known as Takeda G protein-coupled receptor 5, TGR5) (Donkers et al, 2019; Keitel et al, 2019; Kecman et al, 2020). The intestinal GPBAR1 is important in the regulation of glucose metabolism and insulin resistance (Keitel et al, 2019). The development of combined FXR antagonists/ GPBAR1 agonists might provide a synergistic therapeutic strategy in the regulation of glucose homeostasis mediated by intestinal endocrine cells (Downes et al, 2003; Han, 2018; De Marino et al, 2019; Di Leva et al, 2019; Donkers et al, 2019)
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