Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

Bass, Jonathan Y.; Caravella, Justin A.; Chen, Lihong; Creech, Katrina L.; Deaton, David N.; Madauss, Kevin P.; Marr, Harry B.; McFadyen, Robert B.; Miller, A. Whitman; Mills, Wendy Y.; Navas, Frank; Parks, Derek J.; Smalley, Terrence L.; Spearing, Paul K.; Todd, Dan; Williams, Shawn P.; Wisely, G. Bruce

doi:10.1016/j.bmcl.2010.12.089

Cited by 57 publications

(43 citation statements)

References 42 publications

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“…9-11 To determine whether the FXRE in the Srebp-2 locus is functional and regulates both Srebp-2 and miR-33 expression, we treated wild-type (C57BL/6) mice with a single dose of GSK2324, a potent and specific FXR agonist. 13, 17, 18 Srebp-2 mRNA levels were increased significantly after 2 and 4 hours of GSK2324 treatment (Fig. 1B), consistent with direct regulation by FXR.…”

Section: Resultssupporting

confidence: 71%

The Nuclear Receptor FXR Uncouples the Actions of miR-33 From SREBP-2

Tarling

Ahn

Vallim

2015

ATVB

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Objective To determined whether activation of FXR alters cellular and plasma cholesterol homeostasis as a result of regulation of Srebp-2 and miR-33. Approach and Results ChIP-seq data identified an FXR-response element within intron 10 of the Srebp-2 gene. Consistent with this observation, treatment of mice with FXR-specific agonists (GSK2324 or GW4064) rapidly increased hepatic levels of Srebp-2 mRNA, pSREBP-2 protein, and miR-33. Further, miR-33 targets, that include ABCA1, NSF and CPT1, were all reduced in GSK2324-treated mice. In contrast, neither nSREBP-2 protein, nor SREBP-2 target genes were induced following FXR activation. The inability to process pSREBP-2 to nSREBP-2 is likely a consequence of induction of INSIG-2a by FXR agonists. Finally, we show that FXR-dependent induction of both Srebp-2 and miR-33 is ablated in Scap−/− mice that lack nSREBP-2. Conclusions We demonstrate that activation of FXR uncouples the expression of nSREBP-2 and miR-33, and the regulation of their respective target genes. Further, we conclude that the FXR agonist-dependent increase in miR-33 requires transcription of the Srebp-2 gene.

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Section: Resultssupporting

confidence: 71%

The Nuclear Receptor FXR Uncouples the Actions of miR-33 From SREBP-2

Tarling

Ahn

Vallim

2015

ATVB

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“…While the mechanisms regulating Cyp7a1 expression have been extensively studied, much less is known about how FXR represses Cyp8b1 or whether FXR regulates the expression of other genes involved in the two bile acid synthetic pathways. In our initial studies we treated wild-type and Fxr −/− mice (KO) for 3 days with either GW4064, a widely used FXR agonist (Maloney et al, 2000), or GSK2324 a water-soluble derivative of GW4064 that exhibits increased potency (Bass et al, 2011). As expected, both agonists led to robust repression of both Cyp7a1 and Cyp8b1 in wild-type, but not Fxr −/− mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism

et al. 2015

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Summary Specific bile acids are potent signaling molecules that modulate metabolic pathways affecting lipid, glucose and bile acid homeostasis and the microbiota. Bile acids are synthesized from cholesterol in the liver, and the key enzymes involved in bile acid synthesis (Cyp7a1, Cyp8b1) are regulated transcriptionally by the nuclear receptor FXR. We have identified an FXR-regulated pathway upstream of a transcriptional repressor that controls multiple bile acid metabolism genes. We identify MafG as an FXR target gene and show that hepatic MAFG overexpression represses genes of the bile acid synthetic pathway, and modifies the biliary bile acid composition. In contrast, loss-of-function studies using MafG+/− mice causes de-repression of the same genes with concordant changes in biliary bile acid levels. Finally, we identify functional MafG response elements in bile acid metabolism genes using ChIP-Seq analysis. Our studies identify a molecular mechanism for the complex feedback regulation of bile acid synthesis controlled by FXR.

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“…For example, obeticholic acid (i.e., INT-747), a potent selective FXR agonist, is in phase III trials for primary biliary cirrhosis (Pellicciari et al, 2005). Also, the hepatoprotective effects of GW4064 and its analogs have been shown in cholestatic rats and mice with gallstones (Liu et al, 2003;Moschetta et al, 2004;Akwabi-Ameyaw et al, 2008;Bass et al, 2011;Porez et al, 2012). Our results suggest that drugdrug interactions between CYP2D6 substrates and FXR agonists may occur if these FXR agonists are approved and clinically used.…”

Section: D B Amentioning

confidence: 84%

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

2015

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Cytochrome P450 2D6 (CYP2D6) is a major drug-metabolizing enzyme responsible for eliminating approximately 20% of marketed drugs. Studies have shown that differential transcriptional regulation of CYP2D6 may contribute to large interindividual variability in CYP2D6-mediated drug metabolism. However, the factors governing CYP2D6 transcription are largely unknown. We previously demonstrated small heterodimer partner (SHP) as a novel transcriptional repressor of CYP2D6 expression. SHP is a representative target gene of the farnesoid X receptor (FXR). The objective of this study is to investigate whether an agonist of FXR, 3-(2,6-dichlorophenyl)-4-(39-carboxy-2-chlorostilben-4-yl)oxymethyl-5-isopropylisoxazole (GW4064), alters CYP2D6 expression and activity. In CYP2D6-humanized transgenic mice, GW4064 decreased hepatic CYP2D6 expression and activity (by 2-fold) while increasing SHP expression (by 2-fold) and SHP recruitment to the CYP2D6 promoter. CYP2D6 repression by GW4064 was abrogated in Shp(2/2);CYP2D6 mice, indicating a critical role of SHP in CYP2D6 regulation by GW4064. Also, GW4064 decreased CYP2D6 expression (by 2-fold) in primary human hepatocytes, suggesting that the results obtained in CYP2D6-humanized transgenic mice can be translated to humans. This proof of concept study provides evidence for CYP2D6 regulation by an inducer of SHP expression, namely, the FXR agonist GW4064.

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Conformationally constrained farnesoid X receptor (FXR) agonists: Heteroaryl replacements of the naphthalene

Cited by 57 publications

References 42 publications

The Nuclear Receptor FXR Uncouples the Actions of miR-33 From SREBP-2

The Nuclear Receptor FXR Uncouples the Actions of miR-33 From SREBP-2

MAFG Is a Transcriptional Repressor of Bile Acid Synthesis and Metabolism

Farnesoid X Receptor Agonist Represses Cytochrome P450 2D6 Expression by Upregulating Small Heterodimer Partner

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