Farnesoid X receptor antagonist exacerbates dyslipidemia in mice

Amano, Yuichiro; Yamakawa, Hiroko; Yonemori, Kazuko; Shimada, Mitsuyuki; Tozawa, Ryuichi

doi:10.1016/j.pharep.2017.07.010

Cited by 5 publications

(1 citation statement)

References 35 publications

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“…Interestingly, all these compounds showed full FXR selectivity, as they did not activated/ inhibited the other tested NRs (Tables 1 and 2). FXR ligand specificity is the important observation, considering the beneficial effects of FXR ligands in cholestasis and hypercholesterolemia (Jonker et al, 2012;Amano et al, 2018;Keitel et al, 2019).…”

Section: Basal and Maximal Activity Of Hg5ln Gal4-nrs Cellsmentioning

confidence: 99%

Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines

et al. 2020

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To characterize human nuclear receptor (NR) specificity of synthetic pharmaceutical chemicals we established stable cell lines expressing the ligand binding domains (LBDs) of human FXR, LXRa, LXRb, CAR, and RORg fused to the yeast GAL4 DNA binding domain (DBD). As we have already done for human PXR, a two-step transfection procedure was used. HeLa cells stably expressing a Gal4 responsive gene (HG5LN cell line) were transfected by Gal4-NRs expressing plasmids. At first, using these cell lines as well as the HG5LN PXR cells, we demonstrated that the basal activities varied from weak (FXR and LXRs), intermediate (PXR), to strong (CAR and RORg), reflecting the recruitment of HeLa co-regulators in absence of ligand. Secondly, we finely characterized the activities of commercially available FXR, LXRa, LXRb, CAR, RORg, and PXR agonists/antagonists GW4064,

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Section: Basal and Maximal Activity Of Hg5ln Gal4-nrs Cellsmentioning

confidence: 99%

Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines

et al. 2020

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Antidyslipidemic potential of a novel farnesoid X receptor antagonist in a hamster model of dyslipidemia: Comparative studies of other nonstatin agents

Shinozawa

Amano

Yamakawa

et al. 2018

Pharmacology Res & Perspec

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We attempted to clarify the therapeutic capability of antagonists of the farnesoid X receptor (FXR), a nuclear receptor that regulates lipid and bile acid metabolism. Herein, we report the antidyslipidemic effects of a novel synthesized FXR antagonist, compound‐T1, utilizing a dyslipidemic hamster model. Compound‐T1 selectively inhibited chenodeoxycholic acid‐induced FXR activation (IC 50, 2.1 nmol·L−1). A hamster model of diet‐induced hyperlipidemia was prepared to investigate the antidyslipidemic effects of compound‐T1 through comparative studies of the nonstatin lipid‐modulating agents ezetimibe, cholestyramine, and torcetrapib. In the hamster model, compound‐T1 (6 mg·kg−1·day−1, p.o.) increased the level of plasma high‐density lipoprotein (HDL)‐cholesterol (+22.2%) and decreased the levels of plasma non‐HDL‐cholesterol (−43.6%) and triglycerides (−31.1%). Compound‐T1 also increased hepatic cholesterol 7α‐hydroxylase expression and fecal bile acid excretion, and decreased hepatic cholesterol content. Moreover, the hamster model could reflect clinical results of other nonstatin agents. Torcetrapib especially increased large HDL particles compared with compound‐T1. Additionally, in the human hepatoma Huh‐7 cells, compound‐T1 enhanced apolipoprotein A‐I secretion at a concentration close to its IC 50 value for FXR. Our results indicated the usefulness of the hamster model in evaluating FXR antagonists and nonstatin agents. Notably, compound‐T1 exhibited beneficial effects on both blood non‐HDL‐cholesterol and HDL‐cholesterol, which are thought to involve enhancement of cholesterol catabolism and apolipoprotein A‐I production. These findings aid the understanding of the antidyslipidemic potential of FXR antagonists with a unique lipid and bile acid modulation.

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FXR in liver physiology: Multiple faces to regulate liver metabolism

Panzitt

Wagner

2021

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Farnesoid X receptor antagonist exacerbates dyslipidemia in mice

Abstract: It was found that the FXR antagonist, compound-T0 exacerbated dyslipidemia in mice because it enhanced intestinal lipid absorption via acceleration of bile acid excretion.

Cited by 5 publications

References 35 publications

Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines

Assessing the Selectivity of FXR, LXRs, CAR, and RORγ Pharmaceutical Ligands With Reporter Cell Lines

Antidyslipidemic potential of a novel farnesoid X receptor antagonist in a hamster model of dyslipidemia: Comparative studies of other nonstatin agents

FXR in liver physiology: Multiple faces to regulate liver metabolism

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