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Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia

Pataia, Vanessa, McIlvride, Saraid, Papacleovoulou, Georgia, Ovadia, Caroline, McDonald, Julie A. K., Wahlström, Annika, Jansen, Eugène, Adorini, Luciano, Shapiro, David, Marchesi, Julian R., Marschall, Hanns-Ulrich and Williamson, Catherine 2020. Obeticholic acid improves fetal bile acid profile in a mouse model of gestational hypercholanemia. AJP - Gastrointestinal and Liver Physiology 319 (2) , G197-G211. 10.1152/ajpgi.00126.2020

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Abstract

Intrahepatic cholestasis of pregnancy (ICP) is characterized by elevated maternal circulating bile acid levels and associated dyslipidemia. ICP leads to accumulation of bile acids in the fetal compartment, and the elevated bile acid concentrations are associated with an increased risk of adverse fetal outcomes. The farnesoid X receptor agonist obeticholic acid (OCA) is efficient in the treatment of cholestatic conditions such as primary biliary cholangitis. We hypothesized that OCA administration during hypercholanemic pregnancy will improve maternal and fetal bile acid and lipid profiles. Female C57BL/6J mice were fed either a normal chow diet, a 0.5% cholic acid (CA)-supplemented diet, a 0.03% OCA-supplemented diet, or a 0.5% CA + 0.03% OCA-supplemented diet for 1 wk before mating and throughout pregnancy until euthanization on day 18. The effects of CA and OCA feeding on maternal and fetal morphometry, bile acid and lipid levels, and cecal microbiota were investigated. OCA administration during gestation did not alter the maternal or fetal body weight or organ morphometry. OCA treatment during hypercholanemic pregnancy reduced bile acid levels in the fetal compartment. However, fetal dyslipidemia was not reversed, and OCA did not impact maternal bile acid levels or dyslipidemia. In conclusion, OCA administration during gestation had no apparent detrimental impact on maternal or fetal morphometry and improved fetal hypercholanemia. Because high serum bile acid concentrations in ICP are associated with increased rates of adverse fetal outcomes, further investigations into the potential use of OCA during cholestatic gestation are warranted. NEW & NOTEWORTHY We used a mouse model of gestational hypercholanemia to investigate the use of obeticholic acid (OCA), a potent FXR agonist, as a treatment for the hypercholanemia of intrahepatic cholestasis of pregnancy (ICP). The results demonstrate that OCA can improve the fetal bile acid profile. This is relevant not only to women with ICP but also for women who become pregnant while receiving OCA treatment for other conditions such as primary biliary cholangitis and nonalcoholic steatohepatitis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
Publisher: American Physiological Society
ISSN: 0193-1857
Date of First Compliant Deposit: 17 August 2020
Date of Acceptance: 23 June 2020
Last Modified: 18 Aug 2020 14:30
URI: http://orca.cf.ac.uk/id/eprint/134252

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