A Chemical, Genetic, and Structural Analysis of the Nuclear Bile Acid Receptor FXR

Downes, Michael; Verdecia, Mark A.; Roecker, Anthony J.; Hughes, Robert; Hogenesch, John B.; Kast-Woelbern, Heidi R.; Bowman, M.E.; Ferrer, Jean‐Luc; Anisfeld, Andrew M.; Edwards, Peter A.; Rosenfeld, John M.; Alvarez, Jacqueline G.; Noel, Joseph P.; Nicolaou, K. C.; Evans, Ronald M.

doi:10.1016/s1097-2765(03)00104-7

Cited by 345 publications

(315 citation statements)

References 39 publications

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“…UDCA is currently the only effective therapy in cholestasis and, interestingly, has been shown to inhibit CDCA activation of FXR (26,27). UDCA treatment in humans results in induction of MRP4 (28), and our study suggests that the probable mechanism for this induction is via antagonism of FXR.…”

Section: Discussionmentioning

confidence: 59%

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

Stedman

Liddle

Coulter

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

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150

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The nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor have been implicated in regulating bile acid, lipid, carbohydrate, and xenobiotic metabolism. Bile duct ligation was used to increase endogenous bile acids and evaluate the roles of these receptors in modulating cholestatic liver injury. FXR knockout (KO) mice were found to be protected from obstructive cholestasis. Concurrent deletion of FXR also could ameliorate an increase in liver injury that is seen usually in pregnane X receptor KO mice with cholestasis. Mechanisms proposed for this protection include the lowering of bile acid concentrations and altered expression of the hepatic transporters Mdr1, Mdr2, BSEP, and Mrp4. FXR KO mice also exhibit a biphasic lipid profile after bile duct ligation, with an increase in high-density lipoprotein cholesterol and triglycerides by day 6. The expression of apolipoprotein AV was reduced in these mice, implicating FXR in triglyceride regulation. We show that FXR modulates cholestasis by controlling bile acids within the hepatocyte and is involved in bile acid synthesis, bile excretion via BSEP, and serum export via Mrp4. This study strongly suggests a potential clinical role for FXR antagonists in the treatment of obstructive cholestatic liver disorders.bile acids ͉ Mrp4 ͉ pregnane X receptor ͉ apolipoprotein AV ͉ triglycerides C holestatic liver disorders include a spectrum of hepatobiliary diseases of diverse etiologies that are characterized by impaired hepatocellular secretion of bile, resulting in accumulation of bile acids, bilirubin, and cholesterol. Pharmacological therapy for cholestasis is limited, and ursodeoxycholic acid (UDCA) is the only disease-modifying therapy with evidence of efficacy, so new therapeutic approaches are essential.Farnesoid X receptor (FXR) (NR1H4) and pregnane X receptor (PXR) (NR1I2) are nuclear hormone receptors that function as ligand-activated transcription factors. FXR is known to regulate genes involved in lipid and lipoprotein metabolism, including apolipoprotein (apo) AI, apoCII, very low-density lipoprotein (VLDL) receptor, PPAR␣, and the phospholipid transfer protein (1, 2), but the role of FXR in lipid homeostasis remains to be clarified. Other FXR targets include genes involved in bile acid synthesis such as cytochrome P450 7A1 (CYP7A1) and CYP8B1, and bile acid transporters including bile salt export pump (BSEP; ABCB11), sodium-taurocholate cotransporting polypeptide (NTCP; SLC10A1), and intestinal bile acid-binding protein (1, 3). PXR also regulates genes involved in bile acid synthesis, metabolism, and transport, including CYP7A1, CYP3A, sulfotransferase, and Na ϩ -dependent organic anion transporter 2 (Oatp2; Slc21a6) (4, 5).Bile acids are the end products of hepatic cholesterol metabolism, which also act as signaling molecules that regulate their own synthesis and metabolism and other metabolic pathways, via nuclear receptors (1). Bile acids are ligands for both PXR and FXR, with affinities differing for individual bile acids (6, 7). It has...

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Section: Discussionmentioning

confidence: 59%

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

Stedman

Liddle

Coulter

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

150

119

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“…The drug troglitazone also based on a benzopyran scaffold is a known PPARg modulator [85]. Interestingly, a highthroughput screening for FXR inhibitors with a 10,000-member benzopyran library resulted in several hits, as would have been predicted by PSSC [86,87]. In addition, the benzopyran library also yielded ligands for other members of the PSSC cluster, thereby further supporting the application of PSSC in library design.…”

Section: Kaiser Et Almentioning

confidence: 77%

Biology-inspired synthesis of compound libraries

Kaiser

Wetzel

Kumar

et al. 2008

Cell. Mol. Life Sci.

148

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“…The binding of coactivators to the receptor is mediated by nuclear receptor interaction domains (NIDs) on the proteins that contain a conserved LXXLL sequence, and short peptides containing these elements are sufficient for recapitulating these binding interactions (22,23). Before this work, crystal structures of the rat and human FXR LBDs were determined in complex with bile acids and a synthetic ligand, respectively (24,25). We report here the identification of a potent synthetic FXR agonist designated Merck FXR agonist #1 (MFA-1).…”

mentioning

confidence: 99%

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

Soisson

Parthasarathy²,

Adams³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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The farnesoid X receptor (FXR), a member of the nuclear hormone receptor family, plays important roles in the regulation of bile acid and cholesterol homeostasis, glucose metabolism, and insulin sensitivity. There is intense interest in understanding the mechanisms of FXR regulation and in developing pharmaceutically suitable synthetic FXR ligands that might be used to treat metabolic syndrome. We report here the identification of a potent FXR agonist (MFA-1) and the elucidation of the structure of this ligand in ternary complex with the human receptor and a coactivator peptide fragment using x-ray crystallography at 1.9-Å resolution. The steroid ring system of MFA-1 binds with its D ring-facing helix 12 (AF-2) in a manner reminiscent of hormone binding to classical steroid hormone receptors and the reverse of the pose adopted by naturally occurring bile acids when bound to FXR. This binding mode appears to be driven by the presence of a carboxylate on MFA-1 that is situated to make a salt-bridge interaction with an arginine residue in the FXR-binding pocket that is normally used to neutralize bound bile acids. Receptor activation by MFA-1 differs from that by bile acids in that it relies on direct interactions between the ligand and residues in helices 11 and 12 and only indirectly involves a protonated histidine that is part of the activation trigger. The structure of the FXR:MFA-1 complex differs significantly from that of the complex with a structurally distinct agonist, fexaramine, highlighting the inherent plasticity of the receptor.NR1H4 ͉ bile acid receptor ͉ nuclear receptor ͉ x-ray crystallography T he farnesoid X receptor (FXR) plays key roles in regulating cholesterol and bile acid homeostasis (1-4). Central to this function is the ability of bile acid-activated FXR to downregulate the expression of Cyp7a (1, 5, 6), the rate-limiting step in the liver for the conversion of free cholesterol to bile acids, and the up-regulation of the bile salt excretion pump (BSEP), which functions to pump excess bile acids into the gall bladder for eventual fecal excretion (7). Treatment of ob/ob and db/db mice with the synthetic FXR agonist GW4064 significantly improves hypercholesterolemia (8) and lowers free fatty acids (9, 10) and triglyceride levels (11). Additional research has shown that fxr Ϫ/Ϫ mice show insulin resistance and impaired glucose tolerance (8,10,12), and that expression of constitutively active FXR in the liver results in hypoglycemia (10). Similarly, treatment with GW4064 increases insulin sensitivity in ob/ob and db/db mice (8, 10). As such, FXR agonists may have utility in treating metabolic syndrome, a clustering of cardiovascular risk factors characterized by dyslipidemia (elevated triglyceride and low HDL levels), insulin resistance, and poor glucose regulation. Several excellent reviews have summarized the current state of FXR understanding (13,14) and help build the case for the development of FXR modulators for the treatment of diabetes and metabolic syndrome (15).FXR belongs to the lar...

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A Chemical, Genetic, and Structural Analysis of the Nuclear Bile Acid Receptor FXR

Cited by 345 publications

References 39 publications

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

Benefit of farnesoid X receptor inhibition in obstructive cholestasis

Biology-inspired synthesis of compound libraries

Identification of a potent synthetic FXR agonist with an unexpected mode of binding and activation

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