Article date: August 2019
By: Yunjing Zhang, Runqiu Jiang, Xiaojiao Zheng, Sha Lei, Fengjie Huang, Guoxiang Xie, Sandi Kwee, Herbert Yu, Christine Farrar, Beicheng Sun, Aihua Zhao, Wei Jia in Volume 176, Issue 16, pages 2848-2863
Background and Purpose
Ursodeoxycholic acid (UDCA) is the first‐line treatment for primary biliary cholangitis, but its effects on the enterohepatic circulation of bile acid (BA) have been under‐investigated. Therefore, we studied the influence of UDCA on BA enterohepatic circulation in vivo and the mechanisms by which UDCA affects the BA kinetics.
Experimental Approach
Mice were treated with UDCA and other BAs to observe changes in BA pool and BA transporters involved in enterohepatic circulation. Isotope dilution techniques and biochemical analyses were applied to study BA kinetics after oral administration of UDCA, and the mechanism involved.
Key Results
Oral administration of UDCA in mice reduced the overall BA pool and produced a unique BA profile with high‐abundance conjugated UDCA species, including tauroursodeoxycholic acid (TUDCA) and GUDCA. We found increased expression of several main BA transporters in the ileum and liver. BA kinetic experiment showed that feeding UDCA shortened cycling time of BA and accelerated BA enterohepatic circulation. Additionally, we found evidence that the effect of UDCA administration on accelerating BA enterohepatic circulation was due to the inhibition of farnesoid X receptor (FXR) signalling in the ileum and FGF15/19 in the liver.
Conclusion and Implications
Oral administration of UDCA produced a unique BA profile with high‐abundance TUDCA and GUDCA and significantly accelerated BA enterohepatic circulation through the inhibition of intestinal FXR signalling and reduced level of FGF15/19, which in turn, induced the expression of BA transporters in the liver. These findings highlight a critical role for UDCA in maintaining the homeostasis of BA enterohepatic circulation in vivo.
DOI: 10.1111/bph.14705
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