Farnesoid X receptor and fibroblast growth factor 15/19 as pharmacological targets

Maliha, Syeda; Guo, Grace L.

doi:10.1016/j.livres.2021.02.002

Cited by 11 publications

(7 citation statements)

References 63 publications

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“…Regarding hyperlipidemia, FXR overexpression suppresses mRNA levels of SREBP-1c, PEPCK, and G6Pase in the liver to reduce plasma free fatty acid levels to subsequently improve insulin resistance in db / db mice [ 105 ]. FXR is thus considered the pharmaceutical target for developing drugs for non-alcoholic steatohepatitis (NASH) and non-alcoholic fatty liver disease (NAFLD), and synthetic agonists, such as obeticholic acid, tropifexor, cilofexor, EDP-305, and MET-409 have been developed and used in clinical practice or under clinical trials [ 106 , 107 , 108 ].…”

Section: Fxrmentioning

confidence: 99%

“…FGF15/19 is an endocrine hormone secreted from the distal ileum and its production is critically controlled by ileal FXR activity and regulated by a variety of BA species with varying concentrations in the intestinal tract [ 108 , 113 ]. FGF15/19 regulate de novo BA synthesis, cholesterol catabolism, glycogen synthesis, fatty acid metabolism and regeneration in the liver, skeletal muscle mass, and appetite in the brain ( Figure 4 ).…”

Section: Regulation Production and Biological Function Of Fgf15/19mentioning

confidence: 99%

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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

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Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.

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Section: Fxrmentioning

confidence: 99%

Section: Regulation Production and Biological Function Of Fgf15/19mentioning

confidence: 99%

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Katafuchi,

Makishima

2022

IJMS

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“…During NASH development, FXR has been shown to be down-regulated (Wang et al, 2008;Zhang et al, 2009a;Zhang et al, 2009b;Bjursell et al, 2013;Porez et al, 2013;Armstrong and Guo, 2017). Due to the accumulated evidence that FXR plays an important role in modulating lipid homeostasis and suppressing inflammation in NASH development, FXR emerges as a major drug target to treat NASH (Sanyal et al, 2015;Chow et al, 2017;Oseini and Sanyal, 2017;Maliha and Guo, 2021).…”

Section: Bas and Fxr Regulation Of Ba Homeostasismentioning

confidence: 99%

Environmental Chemical Contribution to the Modulation of Bile Acid Homeostasis and Farnesoid X Receptor Signaling

2021

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“…Other compounds possessing a hammer head or trisubstituted isoxazole motif, like GW4064 , (see Figure ), have been very popular owing to their robust and full FXR agonism. However, further evaluation of these compounds, some as monotherapy whereas others in combination, is under evaluation . Data from the ongoing clinical trials will reveal if these therapies deliver robust efficacy as anticipated or a compromised efficacy profile due to potential dose-limiting adverse events.…”

Section: Introductionmentioning

confidence: 99%

“…However, further evaluation of these compounds, some as monotherapy whereas others in combination, is under evaluation. 20 Data from the ongoing clinical trials will reveal if these therapies deliver robust efficacy as anticipated or a compromised efficacy profile due to potential dose-limiting adverse events.…”

Section: ■ Introductionmentioning

confidence: 99%

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

et al. 2022

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While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.

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Farnesoid X receptor and fibroblast growth factor 15/19 as pharmacological targets

Cited by 11 publications

References 63 publications

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis

Environmental Chemical Contribution to the Modulation of Bile Acid Homeostasis and Farnesoid X Receptor Signaling

Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis

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