Ursodeoxycholic acid improves feto-placental and offspring metabolic outcomes in hypercholanemic pregnancy

Abstract

Perturbations in the intrauterine environment can result in lifelong consequences for metabolic health during postnatal life. Intrahepatic cholestasis of pregnancy (ICP) can predispose offspring to metabolic disease in adulthood, likely due to a combination of the effects of increased bile acids, maternal dyslipidemia and deranged maternal and fetal lipid homeostasis. Whereas ursodeoxycholic acid (UDCA) is a commonly used treatment for ICP, no studies have yet addressed whether it can also prevent the metabolic effects of ICP in the offspring and fetoplacental unit. We therefore analyzed the lipid profile of fetal serum from untreated ICP, UDCA-treated ICP and uncomplicated pregnancies and found that UDCA ameliorates ICP-associated fetal dyslipidemia. We then investigated the effects of UDCA in a mouse model of hypercholanemic pregnancy and showed that it induces hepatoprotective mechanisms in the fetal liver, reduces hepatic fatty acid synthase (Fas) expression and improves glucose tolerance in the adult offspring. Finally, we showed that ICP leads to epigenetic changes in pathways of relevance to the offspring phenotype. We therefore conclude that UDCA can be used as an intervention in pregnancy to reduce features of metabolic disease in the offspring of hypercholanemic mothers.

GWAS meta-analysis of intrahepatic cholestasis of pregnancy implicates multiple hepatic genes and regulatory elements

“…The elevated serum bile acids that form the core phenotype are also associated with maternal and fetal dyslipidemia 46 – 48 , and increased rates of gallstone formation 49 . Variation at ABCG8 has previously been linked to gallstone disease and other lipid-related phenotypes 50 , 51 .…”

Intrahepatic cholestasis of pregnancy and maternal dyslipidemia: a systematic review and meta‐analysis

“…In the study by Dann et al, UDCA treatment did not alter maternal plasma lipid concentrations 16 . However, a recent study revealed that UDCA treatment could ameliorate ICP‐associated fetal dyslipidemia 37 . Further animal models have confirmed that UDCA treatment in cholestatic pregnancy can induce hepatoprotective mechanisms in the fetal liver and improve glucose tolerance in adult offspring 37 .…”

“…However, a recent study revealed that UDCA treatment could ameliorate ICP‐associated fetal dyslipidemia 37 . Further animal models have confirmed that UDCA treatment in cholestatic pregnancy can induce hepatoprotective mechanisms in the fetal liver and improve glucose tolerance in adult offspring 37 . UDCA may improve metabolic outcomes in ICP pregnancies, supporting the effectiveness of UDCA treatment in women with ICP.…”

Management of Intrahepatic Cholestasis of Pregnancy: Recommendations of the Working Group on Obstetrics and Prenatal Medicine – Section on Maternal Disorders

“…In addition to the perinatal effects, long-term effects are also suspected. For example, it has recently been shown that treatment with UDCA has a favourable effect on fetal lipid metabolism [134]. UDCA treatment is safe and has few side effects [127].…”

“…Neben den perinatalen Effekten werden auch langfristige Auswirkungen vermutet. So konnte kürzlich der Nachweis erbracht werden, dass die Behandlung mit UDCA den fetalen Lipidstoffwechsel günstig beeinflusst 134 .…”