Abstract
The farnesoid X receptor (FXR) regulates the homeostasis of bile acids, lipids, and glucose. Because endogenous chemicals bind and activate FXR, it is important to examine which xenobiotic compounds would disrupt normal receptor function. We used a cell-based human FXR β-lactamase (Bla) reporter gene assay to profile the Tox21 10K compound collection of environmental chemicals and drugs. Structure-activity relationships of FXR-active compounds revealed by this screening were then compared against the androgen receptor, estrogen receptor α, peroxisome proliferator-activated receptors δ and γ, and the vitamin D receptor. We identified several FXR-active structural classes including anthracyclines, benzimidazoles, dihydropyridines, pyrethroids, retinoic acids, and vinca alkaloids. Microtubule inhibitors potently decreased FXR reporter gene activity. Pyrethroids specifically antagonized FXR transactivation. Anthracyclines affected reporter activity in all tested assays, suggesting non-specific activity. These results provide important information to prioritize chemicals for further investigation, and suggest possible modes of action of compounds in FXR signaling.
Highlights
The farnesoid X receptor (FXR) regulates the homeostasis of bile acids, lipids, and glucose
To rule out FXR antagonist response caused by compound cytotoxicity, a cell viability assay was conducted in the same well as the FXR-bla assay
The ratiometric readouts of FXR-bla assay for measuring FXR activity are based on the b-lactamase-coupled fluorescence resonance energy transfer (FRET) technology[28]
Summary
The farnesoid X receptor (FXR) regulates the homeostasis of bile acids, lipids, and glucose. Gastric bypass surgery has emerged as a potential therapy for diabetes mellitus type 225 where FXR-dependent increase of circulating total bile acids was observed in mice treated with vertical sleeve gastrectomy[26]. These studies suggest that agonists, antagonists, and modulators of FXR could exert protective or adverse effects depending on health states and exposure doses. Compounds identified as FXR-actives were grouped into several clusters based on similarities in chemical structure, drug class, or known biological target. The representative FXR-active clusters were further compared for their selectivity against other tested human nuclear receptors including the androgen receptor (AR), estrogen receptor alpha (ERa), peroxisome proliferator-activated receptor delta (PPARd), peroxisome proliferator-activated receptor gamma (PPARc), and the vitamin D receptor (VDR) to identify FXR-specific chemical scaffolds
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