The Experts below are selected from a list of 7638 Experts worldwide ranked by ideXlab platform
Daniel Merk - One of the best experts on this subject based on the ideXlab platform.
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Molecular tuning of Farnesoid X Receptor partial agonism
Nature communications, 2019Co-Authors: Daniel Merk, Christina Lamers, Sridhar Sreeramulu, Denis Kudlinzki, Krishna Saxena, Verena Linhard, Santosh Lakshmi Gande, Fabian Hiller, Ewa Nilsson, Anna AagaardAbstract:The bile acid-sensing transcription factor Farnesoid X Receptor (FXR) regulates multiple metabolic processes. Modulation of FXR is desired to overcome several metabolic pathologies but pharmacological administration of full FXR agonists has been plagued by mechanism-based side effects. We have developed a modulator that partially activates FXR in vitro and in mice. Here we report the elucidation of the molecular mechanism that drives partial FXR activation by crystallography- and NMR-based structural biology. Natural and synthetic FXR agonists stabilize formation of an eXtended heliX α11 and the α11-α12 loop upon binding. This strengthens a network of hydrogen bonds, repositions heliX α12 and enables co-activator recruitment. Partial agonism in contrast is conferred by a kink in heliX α11 that destabilizes the α11-α12 loop, a critical determinant for heliX α12 orientation. Thereby, the synthetic partial agonist induces conformational states, capable of recruiting both co-repressors and co-activators leading to an equilibrium of co-activator and co-repressor binding.
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Selective Optimization of Pranlukast to Farnesoid X Receptor Modulators.
ChemMedChem, 2018Co-Authors: Simone Schierle, Jurema Schmidt, Astrid Kaiser, Daniel MerkAbstract:Selective optimization of side activities (SOSA) offers an alternative entry to early drug discovery and may provide rapid access to bioactive new chemical entities with desirable properties. SOSA aims to reverse a drug's side activities through structural modification and to design out the drug's original main action. We identified a moderate side activity for the cysteinyl leukotriene Receptor 1 (CysLT1 R) antagonist pranlukast on the Farnesoid X Receptor (FXR). Systematic structural modification of the drug allowed remarkable optimization of its partial FXR agonism to sub-nanonmolar potency. The resulting FXR modulators lack any activity on CysLT1 R and are characterized by high selectivity, high metabolic stability, and low toXicity. With their favorable in vitro profile, these SOSA-derived FXR modulators constitute a new FXR ligand chemotype that appears suitable for further preclinical evaluation.
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Discovery of Novel Molecular Frameworks of Farnesoid X Receptor Modulators by Ensemble Machine Learning.
ChemistryOpen, 2018Co-Authors: Daniel Merk, Francesca Grisoni, Kay Schaller, Lukas Friedrich, Gisbert SchneiderAbstract:Invited for this month's cover picture is the group of Prof. Dr. Gisbert Schneider from the Swiss Federal Institute of Technology (ETH) Zurich (Switzerland). The cover picture illustrates the application of machine-learning methods to eXpand the chemical space of Farnesoid X Receptor (FXR)-targeting small molecules, by employing an ensemble of three complementary machine-learning approaches (counter-propagation artificial neural network, k-nearest neighbor learner, and three-dimensional pharmacophore model). Read the full teXt of their Full Paper at 10.1002/open.201800156.
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Allosteric modulation of the Farnesoid X Receptor by a small molecule.
Scientific reports, 2018Co-Authors: Matthias Gabler, Astrid Kaiser, Manfred Schubert-zsilavecz, Jurema Schmidt, Jan S. Kramer, Julius Pollinger, Julia Weber, Frank Löhr, Ewgenij Proschak, Daniel MerkAbstract:The bile acid activated transcription factor Farnesoid X Receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene eXpression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt eXport protein and small heterodimer partner eXpression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
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nsaids ibuprofen indometacin and diclofenac do not interact with Farnesoid X Receptor
Scientific Reports, 2015Co-Authors: Jurema Schmidt, Dieter Steinhilber, Francamaria Klingler, Ewgenji Proschak, Manfred Schubertzsilavecz, Daniel MerkAbstract:The nuclear Farnesoid X Receptor (FXR) is a ligand activated transcription factor and acts as cellular sensor for bile acids. In this role, FXR is a highly important liver protector and FXR inhibition by antagonists or knockout has shown several deleterious effects. A recent report characterized non-steroidal anti-rheumatic drugs (NSAIDs) such as ibuprofen or diclofenac as FXR antagonists and linked hepatotoXic effects of these drugs with antagonistic activity on FXR. Since this would guide a way to develop safer anti-inflammatory agents by sparing FXR, we intended to further characterize the reported antagonistic activity and intensively investigated ibuprofen, indometacin and diclofenac. However, we conclude that these agents do not interact with FXR and that the reported reduced FXR signaling induced by CDCA in presence of NSAIDs is merely a consequence than a cause of hepatotoXicity.
Manfred Schubert-zsilavecz - One of the best experts on this subject based on the ideXlab platform.
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Allosteric modulation of the Farnesoid X Receptor by a small molecule.
Scientific reports, 2018Co-Authors: Matthias Gabler, Astrid Kaiser, Manfred Schubert-zsilavecz, Jurema Schmidt, Jan S. Kramer, Julius Pollinger, Julia Weber, Frank Löhr, Ewgenij Proschak, Daniel MerkAbstract:The bile acid activated transcription factor Farnesoid X Receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non-alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene eXpression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt eXport protein and small heterodimer partner eXpression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators.
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EXtending the structure-activity relationship of anthranilic acid derivatives as Farnesoid X Receptor modulators: development of a highly potent partial Farnesoid X Receptor agonist.
Journal of Medicinal Chemistry, 2014Co-Authors: Daniel Merk, Roberto Carrasco Gomez, Christina Lamers, Gisbert Schneider, Dieter Steinhilber, Khalil Ahmad, Manfred Schubert-zsilaveczAbstract:The ligand activated transcription factor nuclear Farnesoid X Receptor (FXR) is involved as a regulator in many metabolic pathways including bile acid and glucose homeostasis. Therefore, pharmacological activation of FXR seems a valuable therapeutic approach for several conditions including metabolic diseases linked to insulin resistance, liver disorders such as primary biliary cirrhosis or nonalcoholic steatohepatitis, and certain forms of cancer. The available FXR agonists, however, activate the Receptor to the full eXtent which might be disadvantageous over a longer time period. Hence, partial FXR activators are required for long-term treatment of metabolic disorders. We here report the SAR of anthranilic acid derivatives as FXR modulators and development, synthesis, and characterization of compound 51, which is a highly potent partial FXR agonist in a reporter gene assay with an EC50 value of 8 ± 3 nM and on mRNA level in liver cells.
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Anthranilic acid derivatives as novel ligands for Farnesoid X Receptor (FXR).
Bioorganic & Medicinal Chemistry, 2014Co-Authors: Daniel Merk, Matthias Gabler, Roberto Carrasco Gomez, Daniel Flesch, Thomas Hanke, Astrid Kaiser, Christina Lamers, Oliver Werz, Gisbert Schneider, Manfred Schubert-zsilaveczAbstract:Abstract Nuclear Farnesoid X Receptor (FXR) has important physiological roles in various metabolic pathways including bile acid, cholesterol and glucose homeostasis. The clinical use of known synthetic non-steroidal FXR ligands is restricted due to toXicity or poor bioavailability. Here we report the development, synthesis, in vitro activity and structure–activity relationship (SAR) of anthranilic acid derivatives as novel FXR ligands. Starting from a virtual screening hit we optimized the scaffold to a series of potent partial FXR agonists with appealing drug-like properties. The most potent derivative eXhibited an EC50 value of 1.5 ± 0.2 μM and 37 ± 2% maXimum relative FXR activation. We investigated its SAR regarding polar interactions with the Receptor by generating derivatives and computational docking.
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Characterizing ligands for Farnesoid X Receptor – available in vitro test systems for Farnesoid X Receptor modulator development
Expert opinion on drug discovery, 2013Co-Authors: Daniel Merk, Dieter Steinhilber, Manfred Schubert-zsilaveczAbstract:Introduction: Farnesoid X Receptor (FXR) is an ascending target for metabolic and inflammatory diseases. As a nuclear Receptor, FXR eXhibits many physiological effects in transcription control of several genes. Therefore, the development of synthetic FXR ligands requires elaborate in vitro test systems to characterize novel ligands and to estimate their in vivo activities. Areas covered: This work gathers and describes published in vitro test systems for FXR ligands including cell-based functional assays as well as binding assays. It also evaluates the information which can be provided by these assays. EXpert opinion: In vitro screening of FXR ligands widely relies on reporter gene assays. Additionally, some co-activator re-cruitment assays are described and for the characterization of potent compounds the pattern of affected target genes is evaluated by qPCR. Compared to other nuclear Receptors such as PPARs the variety of test systems is quite low for FXR and might eventually not be enough to sufficient...
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Identification of novel Farnesoid X Receptor modulators using a combined ligand- and structure-based virtual screening
MedChemComm, 2013Co-Authors: Janosch Achenbach, Matthias Gabler, Manfred Schubert-zsilavecz, Ramona Steri, Ewgenij ProschakAbstract:A combined ligand- and structure-based virtual screening has been applied to retrieve novel modulators of the Farnesoid X Receptor (FXR). Four distinct chemotypes eXhibiting partial activation of FXR in a reporter gene assay could be identified. The analysis of the preliminary structure–activity relationships yielded a 3-amino-imidazo[1,2-a]pyridine derivative which showed a maXimum relative FXR activation of about 14% with an EC50 = 480 nM.
Ryuichi Tozawa - One of the best experts on this subject based on the ideXlab platform.
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Farnesoid X Receptor antagonist eXacerbates dyslipidemia in mice
Pharmacological Reports, 2018Co-Authors: Yuichiro Amano, Hiroko Yamakawa, Kazuko Yonemori, Mitsuyuki Shimada, Ryuichi TozawaAbstract:Background The effects of Farnesoid X Receptor (FXR) antagonists on plasma lipid profile in mice have not been investigated thus far. The aim of this study was to investigate the antidyslipidemic effects of an FXR antagonist in dyslipidemic mice, and to clarify the mechanisms underlying the lipid modulatory effect. Methods Compound-T0 (1–100 mg/kg) was orally administered to C57BL/6J mice fed a Western-type diet or low-density lipoprotein Receptor knockout (LDLR-/-) mice fed a Western-type diet for a week, and plasma lipid levels were investigated. Effects on lipid clearance, hepatic triglyceride secretion after Triton WR-1339 challenge, and intestinal lipid absorption were investigated after multiple dosing. Results Compound-T0 significantly increased plasma level of non-high-density lipoprotein cholesterol in both C57BL/6 and LDLR-/- mice; in addition, it significantly increased plasma triglyceride level in LDLR-/- mice. Compound-T0 failed to enhance the clearance of 3,3′-dioctadecylindocarbocyanine (DiI)-labeled LDL in C57BL/6J mice. Although compound-T0 did not affect triglyceride clearance and hepatic triglyceride secretion, it significantly increased intestinal [^3H]cholesterol absorption in LDLR-/- mice. Conclusions 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.
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Farnesoid X Receptor antagonist eXacerbates dyslipidemia in mice.
Pharmacological reports : PR, 2017Co-Authors: Yuichiro Amano, Hiroko Yamakawa, Kazuko Yonemori, Mitsuyuki Shimada, Ryuichi TozawaAbstract:Background The effects of Farnesoid X Receptor (FXR) antagonists on plasma lipid profile in mice have not been investigated thus far. The aim of this study was to investigate the antidyslipidemic effects of an FXR antagonist in dyslipidemic mice, and to clarify the mechanisms underlying the lipid modulatory effect.
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Combinational effects of Farnesoid X Receptor antagonist and statin on plasma lipid levels and low-density lipoprotein clearance in guinea pigs.
Life sciences, 2014Co-Authors: Yuichiro Amano, Mitsuyuki Shimada, Shotaro Miura, Ryutaro Adachi, Eiichiro Ishikawa, Emiko Shinozawa, Ryuichi TozawaAbstract:Abstract Aims We previously reported anti-dyslipidemic effects of a Farnesoid X Receptor antagonist in monkeys. In this study, we compared the cholesterol-lowering effects of single and combined administration of a Farnesoid X Receptor antagonist, compound-T8, and the 3-hydroXy-3-methylglutaryl-coenzyme A reductase inhibitor atorvastatin in a guinea pig model. Main methods Plasma levels of 7α-hydroXy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroXylase activity, were measured after a single administration of compound-T8. The effects of compound-T8 or atorvastatin on plasma cholesterol levels and low-density lipoprotein (LDL) clearance were investigated after 14 or 16 days of repeated dosing, respectively. Fractional catabolic rate of plasma LDL was estimated by intravenous injection of DiI-labeled human LDL. The cholesterol-lowering effects of combination therapy were investigated after 7 days of repeated treatment. Key findings Compound-T8 (10 and 30 mg/kg) increased plasma 7α-hydroXy-4-cholesten-3-one levels in a dose-dependent manner. Single administration of compound-T8 (30 mg/kg) and atorvastatin (30 mg/kg) reduced plasma non-high-density lipoprotein (non-HDL) cholesterol levels by 48% and 46%, respectively, and increased clearance of plasma DiI-labeled LDL by 29% and 35%, respectively. Compound-T8 (10 mg/kg) or atorvastatin (10 mg/kg) reduced non-HDL cholesterol levels by 19% and 25%, respectively, and combination therapy showed an additive effect and lowered cholesterol levels by 48%. Significance Similar to atorvastatin, compound-T8 reduced plasma non-HDL cholesterol levels accompanied with accelerated LDL clearance in guinea pigs. Combination therapy additively decreased plasma non-HDL cholesterol levels. Therefore, monotherapy with a Farnesoid X Receptor antagonist and combination therapy of a Farnesoid X Receptor antagonist with atorvastatin would be attractive dyslipidemia treatment options.
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Antidyslipidemic effects of a Farnesoid X Receptor antagonist in primates.
Life sciences, 2014Co-Authors: Yuichiro Amano, Mitsuyuki Shimada, Shotaro Miura, Ryutaro Adachi, Ryuichi TozawaAbstract:We investigated antidyslipidemic effects of a Farnesoid X Receptor antagonist compound-T3 in non-human primates as a novel treatment approach for dyslipidemia. Cynomolgus monkeys were fed a high-fat diet over 3 weeks. Drugs were administered to the monkeys for a week, and their plasma and fecal lipid parameters were measured. Compound-T3 dose-dependently decreased the plasma non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B levels in high-fat diet-fed cynomolgus monkeys. The plasma levels of 7α-hydroXy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroXylase activity, and total fecal bile acid levels increased, suggesting that the hypocholesterolemic effects would be dependent on the activation of cholesterol catabolism in the liver. Compound-T3 significantly increased the plasma levels of HDL cholesterol and apolipoprotein A-I. In this condition, the cholesterol absorption inhibitor ezetimibe significantly decreased the plasma non-HDL cholesterol levels and increased the fecal cholesterol levels without affecting plasma HDL cholesterol and triglyceride levels. Bile acid sequestrant cholestyramine tended to decrease plasma non-HDL cholesterol and increase fecal bile acid levels. The cholesteryl ester transfer protein inhibitor torcetrapib significantly increased plasma HDL cholesterol levels without affecting plasma non-HDL cholesterol and fecal cholesterol levels. The results of ezetimibe, cholestyramine, and torcetrapib treatments indicate that our high-fat diet fed monkey model would be a preferred animal model for studying non-statin type antidyslipidemic drugs. Compound-T3 significantly decreased non-HDL cholesterol levels and increased HDL cholesterol levels in the monkey model, suggesting that a Farnesoid X Receptor antagonist could be a therapeutic option in human dyslipidemia. Copyright © 2014 Elsevier Inc. All rights reserved.
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Antidyslipidemic effects of a Farnesoid X Receptor antagonist in primates.
Life Sciences, 2014Co-Authors: Yuichiro Amano, Mitsuyuki Shimada, Shotaro Miura, Ryutaro Adachi, Ryuichi TozawaAbstract:Abstract Aims We investigated antidyslipidemic effects of a Farnesoid X Receptor antagonist compound-T3 in non-human primates as a novel treatment approach for dyslipidemia. Main methods Cynomolgus monkeys were fed a high-fat diet over 3 weeks. Drugs were administered to the monkeys for a week, and their plasma and fecal lipid parameters were measured. Key findings Compound-T3 dose-dependently decreased the plasma non-high-density lipoprotein (non-HDL) cholesterol and apolipoprotein B levels in high-fat diet-fed cynomolgus monkeys. The plasma levels of 7α-hydroXy-4-cholesten-3-one, a marker of hepatic cholesterol 7α-hydroXylase activity, and total fecal bile acid levels increased, suggesting that the hypocholesterolemic effects would be dependent on the activation of cholesterol catabolism in the liver. Compound-T3 significantly increased the plasma levels of HDL cholesterol and apolipoprotein A-I. In this condition, the cholesterol absorption inhibitor ezetimibe significantly decreased the plasma non-HDL cholesterol levels and increased the fecal cholesterol levels without affecting plasma HDL cholesterol and triglyceride levels. Bile acid sequestrant cholestyramine tended to decrease plasma non-HDL cholesterol and increase fecal bile acid levels. The cholesteryl ester transfer protein inhibitor torcetrapib significantly increased plasma HDL cholesterol levels without affecting plasma non-HDL cholesterol and fecal cholesterol levels. Significance The results of ezetimibe, cholestyramine, and torcetrapib treatments indicate that our high-fat diet fed monkey model would be a preferred animal model for studying non-statin type antidyslipidemic drugs. Compound-T3 significantly decreased non-HDL cholesterol levels and increased HDL cholesterol levels in the monkey model, suggesting that a Farnesoid X Receptor antagonist could be a therapeutic option in human dyslipidemia.
Frank J. Gonzalez - One of the best experts on this subject based on the ideXlab platform.
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identification of novel pathways that control Farnesoid X Receptor mediated hypocholesterolemia
Journal of Biological Chemistry, 2010Co-Authors: Yanqiao Zhang, Frank J. Gonzalez, Liya Yin, Jody Anderson, Timothy M Willson, Peter A. EdwardsAbstract:Farnesoid X Receptor (FXR) plays important regulatory roles in bile acid, lipoprotein, and glucose homeostasis. Here, we have utilized FXr(-/-) mice and mice deficient in scavenger Receptor class B type I (SR-BI), together with an FXR-specific agonist and adenovirus eXpressing hepatocyte nuclear factor 4alpha or constitutively active FXR, to identify the mechanisms by which activation of FXR results in hypocholesterolemia. We identify a novel pathway linking FXR to changes in hepatic p-JNK, hepatocyte nuclear factor 4alpha, and finally SR-BI. Importantly, we demonstrate that the FXR-dependent increase in SR-BI results in both hypocholesterolemia and an increase in reverse cholesterol transport, a process involving the transport of cholesterol from peripheral macrophages to the liver for eXcretion into the feces. In addition, we demonstrate that FXR activation also induces an SR-BI-independent increase in reverse cholesterol transport and reduces intestinal cholesterol absorption. Together, these data indicate that FXR is a promising therapeutic target for treatment of hypercholesterolemia and coronary heart disease.
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Spontaneous hepatocarcinogenesis in Farnesoid X Receptor-null mice
Carcinogenesis, 2006Co-Authors: Insook Kim, Keiichirou Morimura, Yatrik M. Shah, Qian Yang, Jerrold M. Ward, Frank J. GonzalezAbstract:The Farnesoid X Receptor (FXR) controls the synthesis and transport of bile acids (BAs). Mice lacking eXpression of FXR, designated FXr-null, have elevated levels of serum and hepatic BAs and an increase in BA pool size. Surprisingly, at 12 months of age, male and female FXr-null mice had a high incidence of degenerative hepatic lesions, altered cell foci and liver tumors including hepatocellular adenoma, carcinoma and hepatocholangiocellular carcinoma, the latter of which is rarely observed in mice. At 3 months, FXr-null mice had increased eXpression of the proinflammatory cytokine IL-1β mRNA and elevated β-catenin and its target gene c-myc. They also had increased cell proliferation as revealed by increased PCNA mRNA and BrdU incorporation. These studies reveal a potential role for FXR and BAs in hepatocarcinogenesis.
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Regulation of drug transporters by the Farnesoid X Receptor in mice.
Molecular pharmaceutics, 2004Co-Authors: Tomoji Maeda, Frank J. Gonzalez, Masaaki Miyata, Yasushi Yamazoe, Takafumi Yotsumoto, Daisuke Kobayashi, Takashi Nozawa, Keisuke Toyama, Ikumi TamaiAbstract:The Farnesoid X Receptor (FXR, NR1H4) regulates bile acid and lipid homeostasis by acting as an intracellular bile acid-sensing transcription factor, resulting in altered eXpression of enzymes and transporters involved in bile acid synthesis and transport. Here, we quantitatively analyzed the alterations in eXpression levels of drug transporters, mainly organic anion-transporting polypeptides (oatp), in wild-type and FXR-null mice to evaluate the role of FXR in their eXpression and regulation by cholic acid. Changes in the mRNA amounts in liver, kidney, small intestine, and testis in FXR-null mice fed with or without a supplement of 0.5% cholic acid in the diet were analyzed by semiquantitative RT-PCR. In FXR-null mice, the mRNA levels of oatp1, oatp2, oatp3, and octn1 were lower than those of wild-type mice in kidney and testis, while there was no difference in liver or small intestine. Cholic acid feeding led to significantly decreased levels of eXpression of oatp1 and oct1 and an increased level of eXp...
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The Farnesoid X-Receptor Is an Essential Regulator of Cholesterol Homeostasis
The Journal of biological chemistry, 2002Co-Authors: Gilles Lambert, Frank J. Gonzalez, Marcelo Amar, Grace L. Guo, H. Bryan Brewer, Christopher J. SinalAbstract:To address the importance of the Farnesoid X-Receptor (FXR; NR1H4) for normal cholesterol homeostasis, we evaluated the major pathways of cholesterol metabolism in the FXR-deficient (-/-) mouse model. Compared with wild-type, FXR(-/-) mice have increased plasma high density lipoprotein (HDL) cholesterol and a markedly reduced rate of plasma HDL cholesterol ester clearance. Concomitantly, FXR(-/-) mice eXhibit reduced eXpression of hepatic genes involved in reverse cholesterol transport, most notably, that for scavenger Receptor BI. FXR(-/-) mice also have increased: (i) plasma non-HDL cholesterol and triglyceride levels, (ii) apolipoprotein B-containing lipoprotein synthesis, and (iii) intestinal cholesterol absorption. Surprisingly, biliary cholesterol elimination was increased in FXR(-/-) mice, despite decreased eXpression of hepatic genes thought to be involved in this process. These data demonstrate that FXR is a critical regulator of normal cholesterol metabolism and that genetic changes affecting FXR function have the potential to be pro-atherogenic.
Bart Staels - One of the best experts on this subject based on the ideXlab platform.
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Nuclear bile acid signaling through the Farnesoid X Receptor
Cellular and Molecular Life Sciences, 2015Co-Authors: Claire Mazuy, Bart Staels, Audrey Helleboid, Philippe LefebvreAbstract:Bile acids (BAs) are amphipathic molecules produced from cholesterol by the liver. EXpelled from the gallbladder upon meal ingestion, BAs serve as fat solubilizers in the intestine. BAs are reabsorbed in the ileum and return via the portal vein to the liver where, together with nutrients, they provide signals to coordinate metabolic responses. BAs act on energy and metabolic homeostasis through the activation of membrane and nuclear Receptors, among which the nuclear Receptor Farnesoid X Receptor (FXR) is an important regulator of several metabolic pathways. Highly eXpressed in the liver and the small intestine, FXR contributes to BA effects on metabolism, inflammation and cell cycle control. The pharmacological modulation of its activity has emerged as a potential therapeutic strategy for liver and metabolic diseases. This review highlights recent advances regarding the mechanisms by which the BA sensor FXR contributes to global signaling effects of BAs, and how FXR activity may be regulated by nutrient-sensitive signaling pathways.
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Nuclear bile acid signaling through the Farnesoid X Receptor
Cellular and Molecular Life Sciences, 2015Co-Authors: Claire Mazuy, Bart Staels, Audrey Helleboid, Philippe LefebvreAbstract:Bile acids (BAs) are amphipathic molecules produced from cholesterol by the liver. EXpelled from the gallbladder upon meal ingestion, BAs serve as fat solubilizers in the intestine. BAs are reabsorbed in the ileum and return via the portal vein to the liver where, together with nutrients, they provide signals to coordinate metabolic responses. BAs act on energy and metabolic homeostasis through the activation of membrane and nuclear Receptors, among which the nuclear Receptor Farnesoid X Receptor (FXR) is an important regulator of several metabolic pathways. Highly eXpressed in the liver and the small intestine, FXR contributes to BA effects on metabolism, inflammation and cell cycle control. The pharmacological modulation of its activity has emerged as a potential therapeutic strategy for liver and metabolic diseases. This review highlights recent advances regarding the mechanisms by which the BA sensor FXR contributes to global signaling effects of BAs, and how FXR activity may be regulated by nutrient-sensitive signaling pathways.
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Activation of the Farnesoid X Receptor represses PCSK9 eXpression in human hepatocytes
FEBS letters, 2008Co-Authors: Cédric Langhi, Sandrine Caron, Bart Staels, Cédric Le May, Sanae Kourimate, Michel Krempf, Philippe Costet, Bertrand CariouAbstract:The purpose of this study was to determine whether bile acids (BAs) modulate hepatic pro-protein convertase subtilisin/keXin 9 (PCSK9) gene eXpression. Immortalized human hepatocytes were treated with various BAs. ChenodeoXycholic acid (CDCA) treatment specifically decreased both PCSK9 mRNA and protein contents. Moreover, activation of the BA-activated Farnesoid X Receptor (FXR) by its synthetic specific agonist GW4064 also decreased PCSK9 eXpression. Of functional relevance, coadministration of CDCA counteracted the statin-induced PCSK9 eXpression, leading to a potentiation of LDL Receptor activity. This study suggests that a transcriptional repression of PCSK9 by CDCA or FXR agonists may potentiate the hypolipidemic effect of statins.
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Bile acids, Farnesoid X Receptor, atherosclerosis and metabolic control.
Current opinion in lipidology, 2007Co-Authors: Folkert Kuipers, Johanna H M Stroeve, Sandrine Caron, Bart StaelsAbstract:Purpose of review Bile acids are amphiphilic molecules synthesized from cholesterol eXclusively in the liver that are essential for effective absorption of dietary fat. In addition to this classical role', bile acids act as signalling molecules that control their own metabolism by activating the nuclear Receptor, famesoid X Receptor. Recent findings Recent work demonstrates that famesoid X Receptor eXerts metabolic control beyond bile acid homeostasis, notably effects on HDL, triglyceride and glucose metabolism. Farnesoid X Receptor influences insulin sensitivity of tissues that are not part of the enterohepatic circulation, for eXample, adipose tissue. Certain metabolic effects in the liver appear to be mediated via Farnesoid X Receptor-stimulated release of an intestinal growth factor. In addition, novel signalling pathways independent of Farnesoid X Receptor have been identified that may contribute to bile acid-mediated metabolic regulation. Summary Farnesoid X Receptor represents a potentially attractive target for treatment of various aspects of the metabolic syndrome and for prevention of atherosclerosis. Yet, in view of its pleiotropic effects and apparent species-specificity, it is evident that successful interference of the Farnesoid X Receptor signalling system will require the development of gene-specific and/or organ-specific famesoid X Receptor modulators and eXtensive testing in human models of disease.
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Potential regulatory role of the Farnesoid X Receptor in the metabolic syndrome
Biochimie, 2005Co-Authors: Daniel Duran-sandoval, Jean-charles Fruchart, B. Cariou, Bart StaelsAbstract:Dyslipidemia and gallbladder diseases are two current anomalies observed in patients suffering from the metabolic syndrome and type 2 diabetes. The bile acid-activated nuclear Receptor Farnesoid X Receptor (FXR) controls bile acid as well as lipid metabolism. Recent observations indicate a role for FXR also in carbohydrate metabolism. Hepatic FXR eXpression is altered in diabetic animal models in vivo and regulated by hormones and nutrients in vitro. At the molecular level, FXR activation modifies the transcriptional activity of different transcription factors controlling gluconeogenesis and lipogenesis, thus affecting in concert bile acid, lipid and carbohydrate metabolism. The present review focuses on recent advances in our understanding of the modulation of carbohydrate metabolism by FXR. These observations raise the intriguing possibility for a modulatory role of this Receptor also in the metabolic syndrome.
