Journal
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
Volume 623, Issue -, Pages 162-169Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbrc.2022.07.030
Keywords
Bile acid; Cholestasis; Farnesoid X receptor; Liver; Makisterone A
Categories
Funding
- Natural Science Foundation of Hebei Province, China [C2020206044]
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In this study, Makisterone A (MakA) was identified as a compound that could target FXR, enhance its activity, and alleviate cholestatic liver injury in a mouse model. This suggests that MakA may have potential for the clinical treatment of cholestasis.
Cholestasis is the accumulation of bile acids in the liver due to impaired bile formation, secretion, and excretion caused by infections, drugs, metabolic or genetic diseases. Ursodeoxycholic acid is the only drug approved by the Food and Drug Administration for the treatment of primary biliary cholangitis, but nearly 40% of patients do not adequately respond to this drug and 5-10% show intolerance. The farnesoid X receptor (FXR) plays a key role in bile acid metabolism. Here, by using HERB, a high-throughput experimental and reference-oriented database of herbal medicines, and molecular docking, we identified makisterone A (MakA) as a compound that could target FXR. We showed that MakA enhanced FXR activity in liver cells and expression levels of FXR target genes in vitro. Importantly, MakA intervention alleviated cholestatic liver injury and dysregulation of hepatic bile acid metabolism induced by alpha-naphthylisothiocyanate and, 5-diethoxycarbonyl-1,4-dihydrocollidine in mice. The ability of MakA to improve liver injury in a mouse model suggests that this drug may be used for clinical treatment of cholestasis. (C) 2022 Elsevier Inc. All rights reserved.
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