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

Lofthouse, Emma M.; Torrens, Christopher; Manousopoulou, Antigoni; Nahar, Monica; Cleal, Jane K.; O’Kelly, Ita; Sengers, Bram G.; Garbis, Spiros D.; Lewis, Rohan M.

doi:10.1096/fj.201900015rr

Cited by 36 publications

(29 citation statements)

References 33 publications

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“…If there is an excess accumulation of BAs in the maternal and fetal plasma, a condition known as intrahepatic cholestasis of pregnancy (ICP) develops that poses increased risk for fetal distress, preterm delivery and even spontaneous fetal death (Wikstrom Shemer et al, 2013 ; Lofthouse et al, 2019 ). In ICP, high maternal BA levels result in reverse transfer to the fetus and may also competitively inhibit the transfer of fetal BAs to the mother resulting in the accumulation of maternal BAs in the fetal circulation (Geenes et al, 2014 ).…”

Section: The Alternative Ba Synthetic Pathway For Fetal Liver Metabolism and Growthmentioning

confidence: 99%

“…TCA has been shown to be a vasoactive BA in human placenta capable of raising perfusion pressure in placental cotyledons and constricting chorionic plate arteries causing increased work by the fetal heart to maintain normal placental perfusion. In the same study it was also determined that UDCA was able to block the BA transporter OATP4A1 thus preventing maternal BA uptake across the microvillous membrane of the placental syncytiotrophoblast (Lofthouse et al, 2019 ).…”

Section: The Alternative Ba Synthetic Pathway For Fetal Liver Metabolism and Growthmentioning

confidence: 99%

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Targeting the alternative bile acid synthetic pathway for metabolic diseases

et al. 2020

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The gut microbiota is profoundly involved in glucose and lipid metabolism, in part by regulating bile acid (BA) metabolism and affecting multiple BA-receptor signaling pathways. BAs are synthesized in the liver by multi-step reactions catalyzed via two distinct routes, the classical pathway (producing the 12α-hydroxylated primary BA, cholic acid), and the alternative pathway (producing the non-12α-hydroxylated primary BA, chenodeoxycholic acid). BA synthesis and excretion is a major pathway of cholesterol and lipid catabolism, and thus, is implicated in a variety of metabolic diseases including obesity, insulin resistance, and nonalcoholic fatty liver disease. Additionally, both oxysterols and BAs function as signaling molecules that activate multiple nuclear and membrane receptor-mediated signaling pathways in various tissues, regulating glucose, lipid homeostasis, inflammation, and energy expenditure. Modulating BA synthesis and composition to regulate BA signaling is an interesting and novel direction for developing therapies for metabolic disease. In this review, we summarize the most recent findings on the role of BA synthetic pathways, with a focus on the role of the alternative pathway, which has been under-investigated, in treating hyperglycemia and fatty liver disease. We also discuss future perspectives to develop promising pharmacological strategies targeting the alternative BA synthetic pathway for the treatment of metabolic diseases.

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Section: The Alternative Ba Synthetic Pathway For Fetal Liver Metabolism and Growthmentioning

confidence: 99%

Section: The Alternative Ba Synthetic Pathway For Fetal Liver Metabolism and Growthmentioning

confidence: 99%

Targeting the alternative bile acid synthetic pathway for metabolic diseases

et al. 2020

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“…3 BAs cause vasoconstriction of the placental chorionic veins and can induce fetal arrhythmias leading to fetal asphyxia and intrauterine fetal death. 3,24 Rodent studies have shown that BAs make the myometrium more sensitive to oxytocin and that there is a dose-dependent relationship of BA and myometrial contractility leading to spontaneous preterm birth. 3…”

Section: Pathogenesismentioning

confidence: 99%

“…5,31,32 UDCA decreases the level of BA in fetal amniotic fluid and cord blood by restoring the physiologic placental BA gradient. 23,24,33 Due to the relative rarity of adverse effects on the fetus and variability in early delivery, data confirming a decrease in fetal complications with the use of UDCA are lacking but meta-analyses have suggested an improvement in fetal outcomes. 3,30 In the largest randomized placebo-controlled study of UDCA in ICP to date, there was no difference in fetal outcomes or decrease in maternal serum BA between UDCA and placebo groups but a small decrease in pruritus was found in the UDCA group.…”

Section: Imagingmentioning

confidence: 99%

Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management

Roediger

Fleckenstein

2021

Semin Liver Dis

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Intrahepatic cholestasis of pregnancy (ICP) is a common disorder in the second half of pregnancy characterized by pruritus and elevated serum bile acids (BAs) with spontaneous resolution after delivery. ICP carries a risk of adverse effects on the fetus which correlates with the degree of BA elevation. ICP occurs in genetically susceptible women as the reproductive hormones increase during pregnancy. Ursodeoxycholic acid is still considered the first-line treatment for ICP though it is of unproven benefit in preventing adverse effects on the fetus. Fetal complications, such as stillbirth, increase with gestational age, so preterm delivery is generally performed in cases of severe ICP, defined as BA levels above 40 μmol/L. ICP may recur in future pregnancies and is associated with an increased risk for future hepatobiliary, immune mediated, and cardiovascular diseases. Children born of mothers with ICP have normal development but may have a risk for subsequent metabolic disease.

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“…Lysates were then reduced, alkylated and subjected to trypsin proteolysis. Peptides were isobaric stable isotope labelled using the eight-plex iTRAQ reagent kit and analysed using orthogonal 2-dimensional liquid chromatography (offline alkaline C4 reverse phase and online acidic C18 reverse phase) hyphenated with nanospray ionisation and high-resolution tandem mass spectrometry, as previously reported by the authors [44,45]. Database searching: Unprocessed raw files were submitted to Proteome Discoverer 1.4 (Thermo Fisher Scientific) for target decoy searching against the UniProtKB homo sapiens database (https://www.uniprot.org/proteomes/UP000005640), which comprised of 20,159 entries (release date January 2015), allowing for up to two missed cleavages, a precursor mass tolerance of 10 ppm, a minimum peptide length of 6 and a maximum of two variable (1 equal) modifications of 8-plex iTraq (Y), oxidation (M), deamidation (N, Q), or phosphorylation (S, T, Y).…”

Section: Proteomicsmentioning

confidence: 99%

Placental uptake and metabolism of 25(OH)Vitamin D determines its activity within the fetoplacental unit

Ashley¹,

Simner²,

Manousopoulou³

et al. 2021

Preprint

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Pregnancy 25-hydroxyvitamin D (25(OH)D) concentrations are associated with maternal and fetal health outcomes, but the underlying mechanisms have not been elucidated. Using physiological human placental perfusion approaches and intact villous explants we demonstrate a role for the placenta in regulating the relationships between maternal 25(OH)D concentrations and fetal physiology. Here, we demonstrate active placental uptake of 25(OH)D3 by endocytosis and placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the fetal and maternal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than solely the availability of maternal 25(OH)D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer, including transcriptional activation and inflammatory responses. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta; with widespread effects on the placenta itself. These data show complex and synergistic interplay between vitamin D and the placenta, and inform possible interventions to optimise placental function to better support fetal growth and the maternal adaptations to pregnancy.Significance StatementMaternal 25-hydroxyvitamin D (25(OH)D) is linked to fetal development and subsequent postnatal health, and adverse events in pregnancy, but does not necessarily predict fetal 25(OH)D supply. If, rather than passive diffusion, active placental 25(OH)D uptake and metabolism determine the quantity and type of vitamin D reaching the fetus this becomes a regulated process. Furthermore, 25(OH)D induces placental specific effects on the transcriptome and proteome in patterns relevant to placental function and fetal development, independent of vitamin D transfer. These effects are dependent on the underlying epigenetic landscape. Therefore, maternal 25(OH)D concentrations alone are not sufficient to predict fetal outcome: the synergistic interplay between the placenta and maternal vitamin D becomes critical to ensuring the fetus receives optimal exposure to vitamin D during intrauterine life.

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

Cited by 36 publications

References 33 publications

Targeting the alternative bile acid synthetic pathway for metabolic diseases

Targeting the alternative bile acid synthetic pathway for metabolic diseases

Intrahepatic Cholestasis of Pregnancy: Natural History and Current Management

Placental uptake and metabolism of 25(OH)Vitamin D determines its activity within the fetoplacental unit

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