Geniposidic acid

Geniposidic acid is an orally active FXR modulator and SIRT6 activator. Geniposidic acid binds to the Ser332 and His447 sites on the FXR ligand-binding domain, thereby driving nuclear translocation, coactivator recruitment, and transcription of downstream bile acid and cholesterol metabolism-related genes. Geniposidic acid improves metabolic dysfunction-related fatty liver disease by activating the SIRT6 signaling pathway. Geniposidic acid inhibits inflammation and modulates gut microbiota to alleviate colitis. Geniposidic acid can be used in research on drug-induced liver injury, inflammatory bowel disease, metabolic dysfunction-related fatty liver disease, and metabolic dysfunction-related steatohepatitis^[1][2][3]. In Vitro:Geniposidic acid (25-100 μM; 12 h) activates the nuclear translocation of farnesoid X receptor (FXR) in TP-injured human L02 hepatocytes, upregulates key bile acid synthases and transporters to reduce lipid accumulation, and this activity is absolutely dependent on the expression of FXR^[1].
Geniposidic acid directly binds to the ligand-binding domain of human FXR, with a K_d value of 3.905 × 10⁻⁷ M. It binds to FXR in a dose-dependent manner, with an EC₅₀ of 1.076×10^-8 M^[1].
Geniposidic acid (25-100 μM; 24 h) activates BSEP-mediated transcription of BSEP target genes in human L02 hepatocytes, with Ser332 and His447 residues being critical for this agonist activity^[1].
Geniposidic acid (25-100 μM; 72 h) upregulates the expression and nuclear translocation of miR-19a-3p in TP-damaged human L02 hepatocytes via an FXR-dependent mechanism; miR-19a-3p does not regulate FXR expression, but inhibits LXR-mediated cholesterol synthesis, thereby reducing the expression of cholesterol synthesis genes and lipid droplet accumulation^[1].
Geniposidic acid (25-100 μM) reduces OA/PA-induced lipid accumulation and oxidative stress in primary hepatocytes from wild-type mice in a concentration-dependent manner, which depends on functionally intact SIRT6^[3].
Geniposidic acid (25-100 μM) upregulates the expression and deacetylase activity of SIRT6 in HepG2 cells and mouse primary hepatocytes under both normal and lipotoxic conditions^[3].
Geniposidic acid (0.625-80 μM) binds directly to recombinant human SIRT6, with a K_d value of 6.751 × 10⁻⁸ M^[3].
Geniposidic acid (100 μM) reduces OA+PA-induced lipid accumulation in primary hepatocytes from wild-type mice^[3].
Geniposidic acid (100 μM) upregulates the expression of fatty acid oxidation-related genes *Pparα*, *Cpt1α* and *Cd36* in primary hepatocytes from wild-type mice under lipotoxic conditions^[3]. In Vivo:Geniposidic acid (25-100 mg/kg; i.g.; daily; 6-21 days) in Acetaminophen (HY-66005) and Triptolide (HY-32735) induced liver injury (DILI) mouse models can alleviate liver injury, inflammatory response and bile acid/cholesterol metabolic dysfunction in a concentration-dependent manner by upregulating bile acid synthesis and transport mediators and inhibiting miR-19a-3p-mediated cholesterol synthesis^[1].
Geniposidic acid (25-75 mg/kg; i.g.; daily; 7 days) showed a dose-dependent alleviating effect on DSS-induced colitis in male C57BL/6 mice, including reducing disease activity, restoring colon length, improving colonic tissue morphology, inhibiting the production of pro-inflammatory cytokines, inhibiting NF-κB activation, enhancing the expression of intestinal tight junction proteins, and restoring gut microbiota composition^[2].
Geniposidic acid (75 mg/kg; i.g.; daily; 7 days) showed no visible adverse effects in healthy male C57BL/6 mice and was able to regulate gut microbiota composition^[2].
Geniposidic acid (25-100 mg/kg; i.g.; daily; 4-8 weeks) dose-dependently alleviated metabolic dysfunction-related fatty liver disease induced by high-fat diet (HFD) and MCD in male C57BL/6J mice, with its action dependent on functional liver function^[3].