AI Article Synopsis
- FXR is an important regulator of bile acid metabolism, affecting bile acid synthesis and transport, and is a target for treating liver conditions like cholestasis and nonalcoholic steatohepatitis.
- Researchers isolated 14 new protostane-type triterpenoids and four known compounds from Alisma orientale to create a library for studying their effects on FXR.
- Compound 15 was identified as a potent FXR agonist, with its mechanism of action involving specific amino acid residues, confirmed through various investigative methods.
Article Abstract
Farnesoid X receptor (FXR) is a key regulator in charge of bile acid synthesis, transport, and metabolism. Activation of FXR represses bile acid synthesis and increases its excretion and transport, consequently protecting the liver functions. Thus, FXR is considered as a critical therapeutic target of cholestasis and nonalcoholic steatohepatitis. Herein, we isolated and identified fourteen new protostane-type triterpenoids (1-14) and four known analogues (15-18) from Alisma orientale, and finally constructed a small library of protostane-type triterpenoids (1-70) to investigate their structure-activity relationship with FXR, further leading to obtain compound 15 with potent agonistic activity against FXR (EC = 90 nM). Extensive in vitro investigation confirmed high efficacy of compound 15 against FXR in living cell, and revealed its underlying mechanism for FXR activation (amino acid residues Arg331 and Ser332) by molecular docking and site-directed mutagenesis technology.
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| http://dx.doi.org/10.1016/j.ejmech.2019.111652 | DOI Listing |
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