Transport mechanism of ursodeoxycholic acid in human placental BeWo cells

Xia, Yanming; Dong, Ying; Zhao, Xiaoli; Di, Liuqing; Li, Junsong

doi:10.1002/bdd.2150

Cited by 6 publications

(3 citation statements)

References 36 publications

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“… 37 , 40 We did not quantify UDCA levels in the fetuses in the current study, but in vitro studies have shown that UDCA can be transported across the placenta bidirectionally. 41 It is therefore conceivable that UDCA treatment of the dams during gestation leads to elevated concentrations of UDCA in the circulation and livers of Cyp2c70 -/- fetuses.…”

Section: Discussionmentioning

confidence: 99%

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids

Vries

Palmiotti

et al. 2022

Pediatr Res

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Background Cyp2c70-/- mice with a human-like bile acid (BA) composition display features of neonatal cholestasis. We assessed whether perinatal ursodeoxycholic acid (UDCA) exposure prevents neonatal cholestasis in Cyp2c70-/- mice and reduces cholangiopathy development later in life. Methods Cyp2c70+/- males were crossed with Cyp2c70+/- females fed either a regular chow diet or a 0.1% UDCA-containing diet during breeding, gestation, and suckling. Cholestasis and liver function parameters were assessed in their Cyp2c70-/- and wild-type offspring at 3 and 8 weeks of age. Results Three-week-old Cyp2c70-/- pups showed features of neonatal cholestasis, including elevated plasma BAs and transaminases, which were completely prevented in Cyp2c70-/- pups upon perinatal UDCA exposure. In addition, UDCA administration to the dams corrected altered hepatic gene expression patterns in Cyp2c70-/- pups, reduced markers of fibrogenesis and inflammation, and prevented cholangiocyte proliferation. Yet, these beneficial effects of perinatal UDCA exposure were not retained into adulthood upon discontinuation of treatment. Conclusion Perinatal exposure of Cyp2c70-/- mice to UDCA has beneficial effects on liver function parameters, supporting a direct role of BA hydrophobicity in the development of neonatal cholestasis in these mice. However, prevention of neonatal cholestasis in Cyp2c70-/- mice has no long-lasting effects on liver pathophysiology. Impact This is the first study showing that perinatal UDCA exposure prevents features of neonatal cholestasis that are observed in mice with a human-like bile acid composition, i.e., Cyp2c70-/- mice. Perinatal UDCA exposure of Cyp2c70-/- pups leads to UDCA enrichment in their circulating bile acid pool and, consequently, to a reduced hydrophobicity of biliary bile acids. Perinatal UDCA exposure of Cyp2c70-/- pups has no long-lasting effects on the development of cholangiopathy after discontinuation of treatment. The results in this study expand current knowledge regarding acute and long-lasting effects of UDCA treatment in early life.

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Section: Discussionmentioning

confidence: 99%

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids

Vries

Palmiotti

et al. 2022

Pediatr Res

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“…This study sought to determine whether UDCA is transported by OATP4A1, which is known to utilize the placental glutamate gradient to transport TC (11,27). UDCA was found to be an inhibitor of OATP4A1 but did not transstimulate its activity, so it does not appear to be a substrate, as has been suggested by previous studies (28). Because OATP4A1 does not appear to transport UDCA, this raises the possibility that an unknown transporter or mechanism is implicated in the transfer of UDCA to the fetus.…”

Section: Discussionmentioning

confidence: 92%

Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta

et al. 2019

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Intrahepatic cholestasis of pregnancy (ICP) causes increased transfer of maternal bile acids to the fetus and an increased incidence of sudden fetal death. Treatment includes ursodeoxycholic acid (UDCA), but it is not clear if UDCA protects the fetus. This study explores the placental transport of the bile acid taurocholate (TC) by the organic anion–transporting polypeptide, (OATP)4A1, its effects on the placental proteome and vascular function, and how these are modified by UDCA. Various methodological approaches including placental villous fragments and Xenopus laevis oocytes were used to investigate UDCA transport. Placental perfusions and myography investigated the effect of TC on vasculature. The effects of acute TC exposure on placental tissue were investigated using quantitative proteomics. UDCA inhibited OATP4A1 activity in placental villous fragments and oocytes. TC induced vasoconstriction in placental and rat vasculature, which was attenuated by UDCA. Quantitative proteomic analysis of villous fragments showed direct effects of TC on multiple placental pathways, including oxidative stress and autophagy. The effects of TC on the placental proteome and vasculature demonstrate how bile acids may cause fetal distress in ICP. UDCA inhibition of OATP4A1 suggests it will protect the mother and fetus against the vascular effects of TC by inhibiting its cellular uptake. UDCA may protect the fetus in ICP by inhibiting OATP4A1‐mediated bile acid transfer and TC‐induced placental vasoconstriction. Understanding the physiologic mechanisms of UDCA may allow better therapeutic interventions to be designed specifically for the fetus in the future.—Lofthouse, E. M., Torrens, C., Manousopoulou, A., Nahar, M., Cleal, J. K., O'Kelly, I. M., Sengers, B. G., Garbis, S. D., Lewis, R. M. Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta. FASEB J. 33, 8211–8220 (2019). http://www.fasebj.org

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“…At present, no effective treatment modalities are available for ICP, and the administration of ursodeoxycholic acid (UDCA) is a treatment option (Bicocca et al, 2018;Manna et al, 2019;Perez et al, 2006). The mechanism of action of UDCA is related to the displacement of hydrophobic bile acids to protect the hepatocyte membrane (Xia et al, 2018). Studies have reported that UDCA can relieve pruritus and decrease bile acid levels; however, whether it can prevent adverse effects on the fetus remains unproven (Chappell et al, 2019;Kumar and Kulkarni, 2020;Ovadia et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

The role of noncoding RNA and its diagnostic potential in intrahepatic cholestasis of pregnancy: a research update

Xiong,

Tang,

Xing

et al. 2023

Front. Genet.

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Intrahepatic cholestasis of pregnancy (ICP) is a common liver disorder that generally occurs during the second or third trimester of pregnancy. It rarely causes any harm to the mother; however, it can result in short- and long-term complications in the offspring. Therefore, it is crucial to diagnose and treat this condition to avoid poor pregnancy outcomes. The identification of novel markers with potential diagnostic, prognostic, and therapeutic utility in ICP has gained attention. Noncoding RNAs (ncRNAs), including microRNA, long noncoding RNA, and circular RNA, are a type of transcripts that are not translated into proteins. They possess vital biological functions, including transcriptional and translational regulation and DNA, RNA, and protein interactions. The pathogenesis of ICP is related to the aberrant expression of several circulating or placenta-related ncRNAs. In this review, we summarized all recent findings on ncRNAs and ICP and outlined the concepts that form the basis for the early diagnosis and targeted treatment of ICP.

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Transport mechanism of ursodeoxycholic acid in human placental BeWo cells

Cited by 6 publications

References 36 publications

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids

Perinatal exposure to UDCA prevents neonatal cholestasis in Cyp2c70-/- mice with human-like bile acids

Ursodeoxycholic acid inhibits uptake and vasoconstrictor effects of taurocholate in human placenta

The role of noncoding RNA and its diagnostic potential in intrahepatic cholestasis of pregnancy: a research update

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