Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterized by elevated serum bile acids levels. ICP has potentially deleterious consequences for fetus. Although an association between elevated maternal serum bile acids levels and poor fetal outcome has been reported, the underlying mechanisms remain elusive.
The researchers from Prof. CHEN Jianfeng’s group, at Institute of Biochemistry and Cell Biology (SIBCB), Shanghai Institutes for Biological Sciences (SIBS), Chinese Academy of Sciences(CAS), revealed that maternal high serum bile acids can induce placental inflammation and then affect fetal outcome. This work was published in Journal of Molecular Cell Biology.
They found that bile acids induce NF-kappaB（NF-kappaB） pathway activation via G-protein-coupled bile acid receptor 1 (Gpbar1), which upregulated the expression of inflammatory genes in trophoblasts. Consequently, leukocytes are recruited to placenta, resulting in an aberrant placental inflammation.
Further study using radiolabeled ligand binding assay, they found that ursodeoxycholic acid (UDCA), a drug used clinically to treat ICP, could compete with other bile acids for binding with Gpbar1, and thus inhibit bile acid-induced inflammatory response in trophoblasts. In addition, inhibition of NF-κB by andrographolide shows a similar effect with UDCA in inhibiting bile acid-induced inflammatory response.
Finally, with a rat model of obstructive cholestasis, they revealed that both UDCA and andrographolide treatment can benefit placenta and fetal outcome. Notably, andrographolide, which has never been used for ICP treatment, is more effective than UDCA.
This study suggests that anti-inflammation therapy targeting Gpbar1/NF-κB pathway could be effective in suppressing bile acids-induced inflammation and alleviating ICP-associated fetal disorders.
This study entitled “Bile acids evoke placental inflammation by activating Gpbar1/NF-κB pathway in intrahepatic cholestasis of pregnancy” was published online by Journal of Molecular Cell Biology on 8 July, 2016.
The work was supported by grants from the 973 program, National Natural Science Foundation of China, Personalized Medicines-Molecular Signature-based Drug Discovery and Development, the Strategic Priority Research Program of the Chinese Academy of Sciences, Science and Technology Commission of Shanghai Municipality, SKLCB, the CAS/SAFEA International Partnership Program for Creative Research Teams, and the SA-SIBS scholarship program.
AUTHOR CONTACT:
CHEN Jianfeng, Ph.D., Professor
Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences
320 Yueyang Road, Shanghai 200031, China
Tel: +86-21-5492-1142
E-mail: jfchen@sibcb.ac.cn
KEYWORDS:
Fetal outcome; G protein-coupled receptor; maternal cholestasis; placental inflammation; ursodeoxycholic acid
NEWS ABSTRACT:
This study reports that bile acids induce placental inflammation via activating the Gpbar1/PI3K/NF-kB pathway in placenta in ICP, and also importantly, the function and mechanism of UDCA and andrographolide in the management of placental inflammation in ICP. These finds could offer a better solution for clinical management of ICP.
Model for high level serum bile acid-induced placental inflammation in patients with ICP
(Image provided by Prof. CHEN Jianfeng’s group)
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