2. Academic Validation
  3. Python-derived 16α-Hydroxylated Bile Acid, Pythocholic Acid is a ligand for TGR5, not farnesoid X receptors and vitamin D receptors

Python-derived 16α-Hydroxylated Bile Acid, Pythocholic Acid is a ligand for TGR5, not farnesoid X receptors and vitamin D receptors

  • Biochem Biophys Res Commun. 2025 Mar 5:751:151453. doi: 10.1016/j.bbrc.2025.151453.
Nicole Kiaei 1,  Afsin Malik 2,  Sydney O Idahosa 2,  Kevin K Lee 2,  Kaori Endo-Umeda 3,  Makoto Makishima 3,  Akira Kawamura 4,  Sei Higuchi 5
Affiliations

Affiliations

  • 1 John L. Miller Great Neck North High School, Great Neck, NY, 11023, USA; Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
  • 2 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA.
  • 3 Division of Biochemistry, Department of Biomedical Sciences, Nihon University School of Medicine, 30-1 Oyaguchi-Kamicho, Itabashi-ku, Tokyo, 173-8610, Japan.
  • 4 Department of Chemistry, Hunter College of CUNY, New York, NY, 10065, USA.
  • 5 Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, 11439, USA. Electronic address: higuchis@stjohns.edu.
PMID: 39923459 DOI: 10.1016/j.bbrc.2025.151453
Abstract

Bile acids (BAs) are signaling molecules involved in energy expenditure, glucose homeostasis, and immune system regulation via activation of BA receptors, such as Takeda G-Protein-Coupled Receptor 5 (TGR5), Farnesoid X Receptor (FXR), and Vitamin D Receptor (VDR). The structure of BA, especially the hydroxyl group position, plays an important role in exerting its function. Previously, we reported that 16α-hydroxylated BA, also known as pythocholic acid (PCA), has beneficial effects on metabolic function and lipid metabolism in mammals. However, the molecular mechanism of PCA in mammals is yet to be explored because 16α-hydroxylated BA has not been seen in mammals. This study aims to investigate the binding interaction of PCA to human bile acid receptors, TGR5, FXR, and VDR, using a luciferase reporter assay. Luciferase reporter assay showed that PCA and tauro-conjugated-PCA (TPCA) activated TGR5, but did not activate FXR or VDR. Additionally, PCA and TPCA did not show an antagonistic effect on any of the BA receptors. TPCA treatment significantly decreased lipopolysaccharide (LPS)-induced tumor necrosis factor-alpha (TNF-α) expression in mouse peritoneal macrophages, and inhibition of TGR5 by SBI-115 canceled the anti-inflammatory effect of TPCA. Our data suggests that PCA and TPCA are ligands for mammalian TGR5 receptors.

Keywords

Bile acid; Pythocholic acid; TGR5.

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