Farnesoid X receptor (FXR): Structures and ligands

Jiang, Longying; Zhang, Huajun; Xiao, Desheng; Wei, Hudie; Chen, Yongheng

doi:10.1016/j.csbj.2021.04.029

Cited by 123 publications

(97 citation statements)

References 113 publications

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“…Farnesoid X receptor (FXR), a bile acid activated nuclear receptor mainly expressed in liver and intestine, is a key regulator of hepatic bile acid homeostasis, lipoprotein, and glucose metabolism, inflammatory responses, and liver regeneration [205][206][207]. FXR has been shown to exert inihibitory effects on HSCs activation [208][209][210].…”

Section: Agents That Reduce the Activation Of Hscsmentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

Caligiuri

Gentilini

Pastore

et al. 2021

Cells

116

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Chronic liver injury of different etiologies may result in hepatic fibrosis, a scar formation process consisting in altered deposition of extracellular matrix. Progression of fibrosis can lead to impaired liver architecture and function, resulting in cirrhosis and organ failure. Although fibrosis was previous thought to be an irreversible process, recent evidence convincingly demonstrated resolution of fibrosis in different organs when the cause of injury is removed. In the liver, due to its high regenerative ability, the extent of fibrosis regression and reversion to normal architecture is higher than in other tissues, even in advanced disease. The mechanisms of liver fibrosis resolution can be recapitulated in the following main points: removal of injurious factors causing chronic hepatic damage, elimination, or inactivation of myofibroblasts (through various cell fates, including apoptosis, senescence, and reprogramming), inactivation of inflammatory response and induction of anti-inflammatory/restorative pathways, and degradation of extracellular matrix. In this review, we will discuss the major cellular and molecular mechanisms underlying the regression of fibrosis/cirrhosis and the potential therapeutic approaches aimed at reversing the fibrogenic process.

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Section: Agents That Reduce the Activation Of Hscsmentioning

confidence: 99%

Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

Caligiuri

Gentilini

Pastore

et al. 2021

Cells

116

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“…In fact, in May 2021, Food and Drug Administration (FDA) published a safety communication that can be found on fda.gov, stating that FDA restricts use of OCA in PBC patients with advanced cirrhosis, due to risk of serious liver injury. A recent review by Jiang et al describes a full spectrum of small molecules including agonists, partial agonists, and antagonists of FXR, designed to be applied for BA-related liver diseases [58]. The article reveals not only a multitude of various 3D structures of the ligand binding domain of FXR upon binding different types of ligands, but also the structures of steroidal agonists (e.g., OCA, EDP-305, BAR502), nonsteroidal agonists (e.g., GW4064, Nidufexor, Cilofexor, Tropifexor/LJN452), partial agonist (TERN-101, DM175), as well as natural (ivermectin, tuberatolites,) and synthetic (T3, DY268, FLG249) antagonists of FXR [59].…”

Section: Targeting Fxr For Ba Regulation In Cholestasismentioning

confidence: 99%

“…While some of these ligands have shown positive results in clinical studies for treating cholestatic liver diseases, there are still challenges with negative side effects such as high incidence of increased serum LDL, reduced HDL, and pruritus [55,59]. New strategies have been developed to produce more efficient drugs with less adverse symptoms, for example a dual FXR and TGR5 agonist which regulates pathways from both receptors [58,60].…”

Section: Targeting Fxr For Ba Regulation In Cholestasismentioning

confidence: 99%

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Petrescu

DeMorrow

2021

Cells

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Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.

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“…It is indicated that the steroid moiety in the structure of stigmasterol might be crucial in the binding affinity. The residues involved in stigmasterol-FXR interaction were in the ligand-binding domain [39]. This indicated that stigmasterol might act as a competitive activator with a single high-affinity binding site on FXR.…”

Section: Fxr-stigmasterol Dockingmentioning

confidence: 98%

“…Moreover, in the MCF-7 cell line, FXR activation has been assumed to down-regulate breast cancer target genes such as the MRP-1, MDR3, SLC7A5, and aromatase with the inhibition of cell proliferation [34], [36]. Previous studies have also shown that the stigmasterol emerged as a potent FXR agonist in breast cancer cases [36][37][38][39]. In this work, the results from PrestoBlue Assay showed that stigmasterol could inhibit the activities of the MCF-7 cell line, which is consistent with the above findings.…”

Section: Fxr-stigmasterol Dockingmentioning

confidence: 99%

Characterization and Investigation of Stigmasterol Isolated from Rodent Tuber Mutant Plant (<em>Typhonium flagelliforme</em>), Its Molecular Docking as Anticancer on MF-7 Cells

Nf¹,

Ye²,

Assidqi³

et al. 2021

Preprint

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Typhonium flagelliforme is an Indonesian herbal plant used and applied traditionally to treat cancer diseases. Gamma rays have irradiated rodent tuber mutant plant at six doses gray to in-crease the chemical compounds of anticancer activity. The effect of isolated compounds from ro-dent tuber mutant plants has never been studied and published yet. Our study unveiled the poten-tial of stigmasterol as a remarkable cytotoxic agent and the significant contribution of NMR spectroscopy, IR, Mass spectra, QTOF MS towards the isolation and identification of this anti-cancer agent. Stigmasterol was isolated from T. flagelliforme mutant plant. Stigmasterol was more effective against MCF-7 cells with an IC50 value of 0.1623 µM than Cisplatin with IC50 value 13.2 µM. It is the most potential and active fraction in the human breast cancer cell line. The mo-lecular docking study analyzed the chemical profile of stigmasterol to confirm the receptor in agonist binding sites. The prediction of the toxicity of stigmasterol compounds using in silico and analysis of its interaction with the receptor can act as a competitive regulator with a high-affinity binding site on FXR. Stigmasterol has potential as a candidate for an anticancer drug that pro-moting further clinical action.

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Farnesoid X receptor (FXR): Structures and ligands

Abstract: Graphical abstract

Cited by 123 publications

References 113 publications

Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

Cellular and Molecular Mechanisms Underlying Liver Fibrosis Regression

Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury

Characterization and Investigation of Stigmasterol Isolated from Rodent Tuber Mutant Plant (<em>Typhonium flagelliforme</em>), Its Molecular Docking as Anticancer on MF-7 Cells

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