Disease relevance of Ursolvan

• Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels [1].
• Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR) [2].
• The increased levels of CA and CDCA in the infants with liver disease can be explained by cholestasis [3].

High impact information on Ursolvan

• Gallbladder bile was collected at the time of surgery from 33 cholesterol gallstone patients who were divided into three groups: 16 untreated, 9 pretreated with CDCA (400 mg/day), and 8 pretreated with UDCA (600 mg/day) for 1-3 weeks before surgery [4].
• In addition, HNF4 alpha nuclear binding activity is decreased by CDCA and the human HNF4 alpha gene promoter is repressed by CDCA through an SHP-independent mechanism [5].
• Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells [1].
• CONCLUSIONS: Liver cell damage as a result of preservation injury or rejection leads to a reduction of biliary CA, resulting in a decrease of total biliary bile acids and the CA/CDCA ratio in pediatric liver recipients [6].
• Treatment of thyroid cells with CDCA for 72 h inhibited cAMP production stimulated by 50 mU/L TSH or 0.5 mg/L forskolin and also inhibited iodide uptake induced by 0.5 mM 8-bromo cAMP or 0.5 mg/L forskolin [7].

Anatomical context of Ursolvan

• The inhibitory effect of CDCA was detected after 24 h treatment of thyroid cells, and was dependent on the time of exposure up to 72 h [7].
• The results suggest that CDCA increases the sensitivity of isolated mitochondria in vitro to the calcium-dependent induction of the PTP [8].
• In the presence of calcium and phosphate, chenodeoxycholic acid (CDCA) induced a permeability transition in freshly isolated rat liver mitochondria, characterized by membrane depolarization, release of matrix calcium, and osmotic swelling [8].

Associations of Ursolvan with other chemical compounds

• Using this technique, we found that a synthetic bile acid sulfonate, 3alpha,7alpha-dihydroxy-5beta-cholane-24-sulfonate, which was inactive in a FXR response element-driven luciferase assay using CV-1 cells, caused the most potent interaction, comparable to the reaction produced by CDCA [9].

Gene context of Ursolvan

• We investigated the effects of reduced CDCA on FXR target genes in humans [2].
• In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment [1].
• FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE [1].
• Thus, we report on two structurally similar endogenous substances, 3 alpha, 5 beta-THP and CDCA, which inhibit both 11 beta-OHSD and 5 beta-R activity, and which can confer mineralocorticoid actions upon the glucocorticoid, B [10].

References