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.

Department of Internal Medicine 8 University Hospital of Tübingen Tübingen Germany

Department of Pharmacology and Toxicology Faculty of Pharmacy in Hradec Kralove Charles University Hradec Kralove Czechia

Department of Pharmacology Faculty of Medicine in Hradec Kralove Charles University Hradec Kralove Czechia

Department of Physical Chemistry and Biophysics Faculty of Pharmacy in Hradec Kralove Charles University Hradec Kralove Czechia

Faculty of Sciences Charles University Prague Czechia

Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences Prague Czechia

School of Pharmacy University of Eastern Finland Faculty of Health Sciences Kuopio Finland

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