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Novel FXR (farnesoid X receptor) modulators: Potential therapies for cholesterol gallstone disease.

Abstract：

:Metabolic disorders such as diabetes are known risk factors for developing cholesterol gallstone disease (CGD). Cholesterol gallstone disease is one of the most prevalent digestive diseases, leading to considerable financial and social burden worldwide. Ursodeoxycholic acid (UDCA) is the only bile acid drug approved by FDA for the non-surgical treatment of gallstones. However, the molecular link between UDCA and CGD is unclear. Previous data suggest that the farnesoid X receptor (FXR), a bile acid nuclear receptor, may protect against the development of CGD. In studies aimed at identifying the role of FXR, we recently identify a novel chemical tool, 6EUDCA (6-αethyl-ursodeoxycholic acid), a synthetic derivative of UDCA, for studying FXR. We found that 6EUDCA binds FXR stronger than UDCA in a TR-FRET binding assay. This result was supported by computational docking models that suggest 6EUDCA forms a more extensive hydrogen bound network with FXR. Interestingly, neither compound could activate FXR target genes in human nor mouse liver cells, suggesting UDCA and 6EUDCA activate non-genomic signals in an FXR-dependent manner. Overall these studies may lead to the identification of a novel mechanism by which bile acids regulate cell function, and 6EUDCA may be an effective targeted CGD therapeutic.

journal_name

Bioorg Med Chem

journal_title

Bioorganic & medicinal chemistry

authors

Yu DD,Andrali SS,Li H,Lin M,Huang W,Forman BM

doi

10.1016/j.bmc.2016.06.039

subject

Has Abstract

pub_date

2016-09-15 00:00:00

pages

3986-3993

issue

18

eissn

0968-0896

issn

1464-3391

pii

S0968-0896(16)30462-X

journal_volume

24

pub_type

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