Placental Expression of Bile Acid Transporters in Intrahepatic Cholestasis of Pregnancy

Ontsouka, Edgar; Epstein, Alessandra; Kallol, Sampada; Zaugg, Jonas; Baumann, Marc; Schneider, H.; Albrecht, Christiane

doi:10.3390/ijms221910434

Cited by 10 publications

(7 citation statements)

References 28 publications

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“…This implies that OTAP abnormalities can affect bile acid levels ( Dawson et al, 2005 ). Previous studies have focused more on the effect of the expression of OTAPs, such as SLC10A2 and SLCO4A1 , on maternal bile acid levels ( Yan et al, 2015 ; Ontsouka et al, 2021 ). Our present study identified 13 new mutations, including SLC10A2 and Ala310Thr, in the OTAP family from 249 ICP patients.…”

Section: Discussionmentioning

confidence: 99%

“… Yan et al, 2015 confirmed the role of SLCO1B3 in bile acid transport. Ontsouka et al, 2021 reported that placental SLC10A2 , SLCO4A1 , and ABCC2 mRNA levels were positively correlated with bile acid concentrations in ICP patients (). Therefore, considering that women with ICP exhibited elevated serum bile acid levels and that OTAP abnormalities can result in altered bile acid levels, we speculated that mutations in OTAP genes might be present in women with ICP.…”

Section: Introductionmentioning

confidence: 99%

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Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy

et al. 2022

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Background: Intrahepatic cholestasis of pregnancy (ICP) is associated with a high incidence of fetal morbidity and mortality. Therefore, revealing the mechanisms involved in ICP and its association with fetal complications is very important.Methods: Here, we used a whole-exome sequencing (WES) approach to detect novel mutations of organic anion transporting polypeptide (OTAP) genes, ATP-binding cassette transporter (ABC) genes, and receptor genes associated with ICP in 249 individuals and 1,029 local control individuals. Two available tools, SIFT and PolyPhen-2, were used to predict protein damage. Protein structuremodeling and comparison between the reference and modified protein structures were conducted by SWISS-MODEL and Chimera 1.14rc software, respectively.Results: A total of 5,583 mutations were identified in 82 genes related to bile acid transporters and receptors, of which 62 were novel mutations. These novel mutations were absent in the 1,029 control individuals and three databases, including the 1,000 Genome Project (1000G_ALL), Exome Aggregation Consortium (ExAC), and Single-Nucleotide Polymorphism Database (dbSNP). We classified the 62 novel loci into two groups (damaging and probably damaging) according to the results of SIFT and PolyPhen-2. Out of the 62 novel mutations, 24 were detected in the damaging group. Of these, five novel possibly pathogenic variants were identified that were located in known functional genes, including ABCB4 (Ile377Asn), ABCB11 (Ala588Pro), ABCC2 (Ile681Lys and Met688Thr), and NR1H4 (Tyr149Ter). Moreover, compared to the wild-type protein structure, ABCC2 Ile681Lys and Met688Thr protein structures showed a slight change in the chemical bond lengths of ATP-ligand binding amino acid side chains. The combined 32 clinical data points indicate that the mutation group had a significantly (p = 0.04) lower level of Cl ions than the wild-type group. Particularly, patients with the 24 novel mutations had higher average values of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bile acids (TBA), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) than patients with the 38 novel mutations in the probably damaging group and the local control individuals.Conclusion: The present study provides new insights into the genetic architecture of ICP involving these novel mutations.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy

et al. 2022

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“…Most of the fetal pool of BAs is eliminated from the mother’s body via the gastrointestinal tract [ 84 , 85 ]. The identified factors influencing the maintenance of BA balance in the maternal-fetal circulation include: activity of hepatic metabolic pathways involved in the biosynthesis and transformation of BAs in both the mother and the fetus, the rate of BA elimination from the maternal organism, and the transport properties of the placenta [ 81 , 86 ].…”

Section: Bile Acidsmentioning

confidence: 99%

“…Thus far, there is no consensus as to whether an increase in serum BAs precedes clinical symptoms. There have been reports of BAs rising prior to the onset of clinical symptoms or the appearance of other biochemical abnormalities [ 86 , 93 ].…”

Section: Bile Acids In Pregnancy Complicated By Icpmentioning

confidence: 99%

Bile Acids in Intrahepatic Cholestasis of Pregnancy

et al. 2022

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Intrahepatic cholestasis of pregnancy (ICP) is the most common, reversible, and closely related to pregnancy condition characterized by elevated levels of bile acids (BAs) in blood serum and an increased risk of adverse perinatal outcomes. Due to the complex interactions between the mother and the fetus in metabolism and transplacental BAs transport, ICP is classified as a fetal-maternal disease. The disease is usually mild in pregnant women, but it can be fatal to the fetus, leading to numerous complications, including intrauterine death. The pathophysiology of the disease is based on inflammatory mechanisms caused by elevated BA levels. Although ICP cannot be completely prevented, its early diagnosis and prompt management significantly reduce the risk of fetal complications, the most serious of which is unexpected intrauterine death. It is worth emphasizing that all diagnostics and management of ICP during pregnancy are based on BA levels. Therefore, it is important to standardize the criteria for diagnosis, as well as recommendations for management depending on the level of BAs, which undoubtedly determines the impact on the fetus. The purpose of this review is to present the potential and importance of BAs in the detection and rules of medical procedure in ICP.

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“…Finally, a very topical and informative overview highlighting the role of the placenta and the use of low-dose aspirin in the prevention of pre-eclampsia [ 4 , 5 ]. In addition to the reviews, our collection also contains several novel studies covering pre-eclampsia [ 6 , 7 , 8 ]; fetal growth restriction [ 7 , 9 , 10 , 11 ]; calcium signaling [ 12 ]; placental oxidative stress, nutrition, senescence and apoptosis [ 6 , 9 , 13 , 14 , 15 ]; sexual dimorphism [ 16 , 17 , 18 ], intrahepatic cholestasis [ 19 ]; placental vascular modelling [ 20 ]; and placental villous explant culture models [ 21 ].…”

mentioning

confidence: 99%