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Geniposidic Acid Targeting FXR "S332 and H447" Mediated Conformational Change to Upregulate CYPs and miR-19a-3p to

Minqi Fan1,2, Yuanhang Xu1,2, Bingxin Wu1,2

  • 1State Key Laboratory of Traditional Chinese Medicine Syndrome, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, 510006, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|February 25, 2025
PubMed

Insights

Geniposidic acid (GPA) protects against drug-induced liver injury (DILI) by activating the Farnesoid X receptor (FXR). This dual action enhances bile acid metabolism and inhibits cholesterol production, offering a new therapeutic strategy for DILI.

Area of Science:

  • Hepatology
  • Pharmacology
  • Molecular Biology

Background:

  • Drug-induced liver injury (DILI) lacks early detection markers, often leading to severe liver failure.
  • The Farnesoid X receptor (FXR) regulates bile acid and cholesterol metabolism, presenting a potential therapeutic target for DILI.
  • Geniposidic acid (GPA), derived from Gardenia jasminoides, is investigated for its hepatoprotective effects.

Purpose of the Study:

  • To investigate the pathogenesis, markers, and treatment strategies for DILI.
  • To explore the mechanisms of GPA in regulating bile acid and cholesterol metabolism in DILI models.
  • To elucidate the "structure-target" relationship between GPA and FXR in DILI treatment.

Main Methods:

  • Utilized cellular and animal models of acute and chronic DILI induced by acetaminophen and triptolide.
  • Performed lipidomic and bile acid analyses to assess GPA's effects.
  • Employed AAV-shFXR, Fxr-/- mice, molecular assays, miRNA sequencing, and RNA-pulldown assays to determine GPA's molecular targets and mechanisms.

Main Results:

  • GPA alleviates DILI by enhancing bile acid synthesis and transport through FXR activation.
  • GPA targets specific sites on the FXR ligand-binding domain, promoting FXR nuclear translocation and activating CYPs for bile acid metabolism.
  • GPA-activated FXR upregulates miR-19a-3p, which inhibits cholesterol production by binding to LXR 3'UTR.

Conclusions:

  • GPA exhibits a dual mechanism of action against DILI: promoting bile acid metabolism via FXR and inhibiting cholesterol synthesis through miR-19a-3p.
  • The study reveals a novel GPA-FXR "structure-target" interaction.
  • These findings provide a scientific basis for developing FXR-targeted therapies for DILI.
Keywords:
Farnesoid X receptor (FXR)bile acid metabolismcholesterol productiondrug‐induced liver injurymiR‐19a‐3p

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