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UDCA Administration in Cholestatic Pregnancy Can Ameliorate Dysregulated Metabolic Profile of the Fetus and Offspring

Georgia Papacleovoulou1, Vanessa Pataia1, Syed Qadri1, Shadi Abu-Hayyeh1, Saraid Mcilvride, Annika Wahlstroem2, Eugene Jansen3, Hanns-Ulrich

Marschall2 and Catherine Williamson1

1. Maternal and Fetal Disease Group, Division of Women’s Health, King’s College London, UK 2. Department of Molecular and Clinical Medicine, University of Gothenburg, Sweden

3. National Institute for Public Health and the Environment, Bilthoven, Netherlands

Women’s Health Academic Centre

Introduction

The intrauterine environment contributes to the development of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that is characterised by hypercholanaeimia (increased maternal bile acid (BA) levels)1 and dyslipidaemia2. We established that cholestasis in human and mouse causes metabolic dysregulation of the offspring that is triggered by cholestasis-associated dyslipidaemia in the fetoplacental unit3. We hypothesise that ursodeoxycholic acid (UDCA) that is the commonest drug to treat ICP, improves the abnormal metabolic phenotype of the fetus and the offspring of affected pregnancies

Figure 1: There are increased levels of tauro-conjugated bile acids in the fetal serum compared to maternalserum. UDCA can reverse CA-induced tauro-BA in the maternal but not in the fetal serum. *p<0.05; TCA: tauro-cholic acid, TDCA: tauro-deoxycholic acid

maternal serum

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Figure 2: UDCA reversed CA-induced lipids in maternal serum and liver. *p<0.05; Chol: cholesterol, FFA: free fatty acids, TG: triglycerides

Figure 6: Western diet (WD)-fed offspring exposed to UDCA in utero had improved glucose tolerance compared to offspring of CA-fed mothers; n≥4, *p<0.05; NC WD: WD-fed offspring from NC mother; CA WD: WD-fed offspring from CA mother; CA+UDCA WD:WD-fed offspring from CA+UDCA mother

Administration of Rx UDCA in maternal cholestasis

Improves maternal hypercholanaemia and dyslipidaemia

Improves fetoplacental dyslipidaemia, probably through hepatoprotective mechanisms

Improves glucose tolerance in the offspring

Schematic 1: Experimental design

Effects of UDCA on tauro-conjugated bile acid levels

0.5% CA feeding 0.5% CA+UDCA feeding

Maternal liver, placenta, fetal liver

Maternal and fetal serum

Biochemical measurements

Gene expression of metabolic genes

BA homeostasis

Cholesterol homeostasis

FFA homeostasis

Normal chow (NC) used as controls; n=5 / group

Effects of UDCA on maternal lipid concentrations

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Effects of UDCA on glucose response in the offspring

1. Geenes and Williamson Obstet Gynecol. 2014 Jul;124(1):120-33; 2. Dannet al., Obstet Gynecol. 2006 Jan;107(1):106-14; 3. Papacleovoulou et al., J Clin Invest. 2013 Jul 1;123(7):3172-81

References

Acknowledgements

I would like to thank all the members of the Maternal and FetalDisease group for their support and advice. Also, thank you to people at BSU, KCL

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NC: normal chowCA: cholic acidUDCA: ursodeoxycholic acidBA: Bile AcidsFFA: Free Fatty Acids

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Figure 3: UDCA reversed CA-induced FFA in fetal liver and CA-induced cholesterol in placenta. *p<0.05; Chol: cholesterol, FFA: free fatty acids, TG: triglycerides

Effects of UDCA on fetal liver BA transport genes

Effects of UDCA on fetal lipid gene expression

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Figure 5: UDCA reversed the CA-induced Fas (rate-limited step in FA synthesis), but not Hmgcr (rate-limited step in cholesterol synthesis) in the fetl liver; *p<0.05

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Figure 4: UDCA increased the BA transporters Mrp2 and Oatp1a1 in the fetal liver; *p<0.05

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