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Basic science
P42 Cholestatic pregnancy alters cholesterol and lipid transport to the fetal circulation, affecting lipid metabolism of the fetus
  1. G Papacleovoulou1,
  2. A Milona1,
  3. B Owen2,
  4. E Jansen3,
  5. C Williamson1
  1. 1Institute of Reproductive and Developmental Biology, Imperial College London, UK
  2. 2Howard Hughes Medical Institute, University of Texas, USA
  3. 3National Institute for Public Health and the Environment, USA

Abstract

Introduction Altered nutritional environment during intrauterine life may permanently affect tissue homeostasis of the fetus that can increase susceptibility of offspring to the development of disease in later life. Intrahepatic cholestasis of pregnancy (ICP) is a liver-specific disease of pregnancy that is characterised by increased bile acid (BA) levels in the maternal serum.

Aim We aimed to establish the effects of exposure of the fetus to increased BA levels as a result of maternal cholestasis in the mouse.

Method C57BL/6 mice were used for our studies (six mice/group). Cholestatic pregnancy was achieved with addition of 0.5% of cholic acid (CA) in the standard diet (ERD) 1 week before mating and up to day 18 of gestation when animals sacrificed. Biochemical measurements and gene and protein expression analyses took place in the maternal and fetal serum as well as maternal liver, fetal liver and placenta.

Results Consistent with a cholestatic profile, fetuses from CA-fed mothers were characterised by raised BA levels in the serum (p<0.05). Also, the hepatic BA receptor, Fxr, was activated as indicated by alterations in its target genes (reduced Cyp7a1, increased Shp and Bsep). As a result of cholestasis, fetal hepatic cholesterol and fatty acid biosynthesis were induced as proved by up-regulation of Srebp2, Srebp1c, Hmgcr and Fas (p<0.05). Moreover, fetal hepatic cholesterol and triglycerides were increased relative to the levels of fetuses of ERD-fed mothers. Comparison between the placentas of ERD- vs CA-fed mothers revealed that CA-fed placentas had increased expression levels of lipogenic-related genes such as Adrp, Ldlr and Acat-2 (p<0.05), accompanied by raised placental cholesterol and decreased ApoB (p<0.05).

Conclusion Cholestatic pregnancy leads to fetal cholestasis and increased hepatic cholesterol and fatty acid biosynthesis. The placental gene expression and biochemical profile imply that cholesterol accumulates in placenta instead of crossing into the fetal environment. Therefore, increased fetal hepatic cholesterol and fatty acid biosynthesis could be an adaptive mechanism of the fetus to fulfil their developmental nutritional demands. This may have adverse effects in later life of the offspring.

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