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  3. The farnesoid X receptor (FXR) antagonist 7β-isopropylchenodeoxycholic acid improves glucose metabolism in mice on a Western diet

The farnesoid X receptor (FXR) antagonist 7β-isopropylchenodeoxycholic acid improves glucose metabolism in mice on a Western diet

  • Pharmacol Res. 2025 Sep 11:221:107950. doi: 10.1016/j.phrs.2025.107950.
Alzbeta Stefela 1,  Klara Dohnalova 2,  Hana Lastuvkova 3,  Josef Skoda 4,  Maria Bajnokova 4,  Sophie Lestavel 5,  Veronique Touche 5,  Miroslav Kaspar 6,  Eva Kudova 6,  Milos Hroch 7,  Stanislav Micuda 3,  Otto Kucera 8,  Petr Pavek 9
Affiliations

Affiliations

  • 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic; Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
  • 2 Czech Centre for Phenogenomics, Institute of Molecular Genetics of the Czech Academy of Sciences, Prague, Czech Republic; 1st Medical Faculty, Charles University, Prague, Czech Republic.
  • 3 Department of Pharmacology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
  • 4 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
  • 5 University Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille F-59000, France.
  • 6 Institute of Organic Chemistry and Biochemistry of the Czech Academy of Sciences, Prague, Czech Republic.
  • 7 Department of Medical Biochemistry, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
  • 8 Department of Physiology, Faculty of Medicine in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic.
  • 9 Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University, Hradec Kralove, Czech Republic. Electronic address: pavek@faf.cuni.cz.
PMID: 40945669 DOI: 10.1016/j.phrs.2025.107950
Abstract

The significant roles of the farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) in regulating metabolic pathways have recently been demonstrated. However, the precise effects of FXR inhibitors on glucose metabolism remain to be elucidated. In this study, we examined the impact of 7β-isopropylchenodeoxycholic acid (7β-ipCDCA), a dual FXR antagonist and TGR5 agonist, on impaired glucose metabolism in mice fed a Western diet. The dual FXR antagonistic/TGR5 agonistic activity of 7β-ipCDCA was confirmed through gene reporter assays. We evaluated its effects on glucose homeostasis using a glucose tolerance test in C57BL/6 mice fed a Western diet supplemented with sugar in drinking water for 24 weeks. The glucose-lowering mechanism was further investigated by measuring GLP-1 release, mRNA expression of glucose transporters, and relevant genes involved in glucose metabolism in intestinal, hepatic, white adipose, and kidney tissues, and in human NCI-H716 and murine GLUTag L cell lines. Additionally, bile acid metabolome and hepatic lipidome analyses were conducted. Results showed that 7β-ipCDCA improves glucose homeostasis altered by a Western diet in mice via enhanced GLP-1 secretion and decreased expression of glucose transporters in the ileum and kidneys. While its impact on liver function was marginal, 7β-ipCDCA increased plasma taurocholic acid levels. Furthermore, 7β-ipCDCA elevated hepatic triacylglycerols in mice on a chow diet, whereas mice on the Western diet were protected from triacylglycerol accumulation. This study highlights the role of FXR in regulating intestinal glucose transporters and GLP-1 secretion, emphasizing the therapeutic potential of combined FXR antagonists/TGR5 agonists in managing hyperglycemia.

Keywords

Farnesoid X receptor antagonist; Glucagon-like peptide 1; Glucose transporters; TGR5.

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