Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets

Signal Transduction and Targeted Therapy, Journal Year: 2024, Volume and Issue: 9(1)

Published: April 25, 2024

Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. acid signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, neoplastic conditions, strongly influencing health disease. No curative treatment exists for any bile influenced disease, while most promising well-developed therapeutic was recently rejected by FDA. Here, we provide bottom-up approach on mechanistically explaining their biochemistry, physiology, pharmacology at canonical non-canonical receptors. Using this mechanistic model explain how abnormal physiology drives disease pathogenesis, emphasizing ceramide synthesis may serve unifying pathogenic feature cardiometabolic diseases. We an in-depth summary pre-existing receptor modulators, shortcomings, propose solutions they be remedied. Lastly, rationalize novel targets further translational drug discovery future perspectives. Rather than dismissing therapeutics due to recent setbacks, believe that there is immense clinical potential high likelihood success therapeutics.

Language: Английский

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A Current Understanding of FXR in NAFLD: The multifaceted regulatory role of FXR and novel lead discovery for drug development

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 175, P. 116658 - 116658

Published: May 2, 2024

The global prevalence of nonalcoholic fatty liver disease (NAFLD) has reached 30 %, with an annual increase. incidence NAFLD-induced cirrhosis is rapidly rising and become the leading indicator for transplantation in US. However, there are currently no US Food Drug Administration-approved drugs NAFLD. Increasing evidence underscores close association between NAFLD bile acid metabolism disorder, highlighting feasibility targeting signaling pathway treatment. farnesoid X receptor (FXR) endogenous acids that exhibits favorable effects ameliorating metabolic imbalance acids, lipid disorders, disruption intestinal homeostasis, all which key characteristics NAFLD, making FXR a promising therapeutic target present review provides comprehensive overview diverse mechanisms through improves particular emphasis on its involvement regulating homeostasis recent advancements drug development

Language: Английский

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Discovery of farnesoid X receptor antagonists from Salvia miltiorrhiza based on virtual screening and activity verification

Bioorganic & Medicinal Chemistry Letters, Journal Year: 2025, Volume and Issue: unknown, P. 130222 - 130222

Published: April 1, 2025

Language: Английский

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FXR Antagonist FLG249 Lowers Hepatic Triacylglycerol and Serum Cholesterol Level in High-Fat Diet-Induced Obese Mice

Biological and Pharmaceutical Bulletin, Journal Year: 2024, Volume and Issue: 47(8), P. 1429 - 1436

Published: Aug. 12, 2024

Farnesoid X receptor (FXR) is a nuclear that regulates the synthesis and enterohepatic circulation of bile acids (BAs). It also lipid carbohydrate metabolism, making FXR ligands potential therapeutic agents for systemic and/or hepatic metabolic disorders. We previously synthesized series antagonists showed oral administration FLG249 reduced expression several target genes in mouse ileum. Here, we investigated effects on metabolism mice fed high-fat diet (HFD). When was administered 4 weeks to HFD-induced obese mice, it altered related BA ceramide fatty acid β-oxidation, improving liver ileum without decreasing body weight. These findings suggest has be low toxicity pharmaceutical compound likely acts as nonsteroidal antagonist improve

Language: Английский

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Design, synthesis and FXR partial agonistic activity of anthranilic acid derivatives bearing aryloxy moiety as therapeutic agents for metabolic dysfunction-associated steatohepatitis

Bioorganic Chemistry, Journal Year: 2024, Volume and Issue: 153, P. 107940 - 107940

Published: Nov. 3, 2024

Language: Английский

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