SFEBES2013 Oral Communications Obesity, metabolism and bone (8 abstracts)
Cholestatic pregnancy programmes metabolic disease in the offspring
Georgia Papacleovoulou 1 , Shadi Abu-Hayyeh 1 , Evanthia Nikolopoulou 1 , Caroline Ovadia 1 , Vanya Nikolova 1 , Marjo-Riitta Jarvelin 1 , Eugene Jansen 2 , Christiane Albrecht 3 , Jose J G Marin 4 , Alex S Knisely 5 & Catherine Williasmon 1
1Imperial College London, London, UK; 2National Institute for Public Health and the Environment, Bilthoven, The Netherlands; 3University of Bern, Bern, Switzerland; 4University of Salamanca, Salamanca, Spain; 5King’s College Hospital, London, UK.
Epidemiological studies have identified the intrauterine environment as a major contributor to increased rates of metabolic disease in adults, but the underlying mechanisms are poorly understood. Intrahepatic cholestasis of pregnancy (ICP) is a common liver disease of pregnancy that affects 0.5–2% pregnant women and is characterised by increased bile acid (BA) levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown.
We analysed the North Finland birth cohort (NFBC) 1985/86 database and found that 16-year-old children of mothers with ICP had altered lipid profiles and increased BMI compared to the offspring of uncomplicated pregnancies. We investigated the effect of maternal cholestasis on the metabolism of adult offspring by using a mouse model of gestational cholestasis. The 18-week-old females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following western diet (WD) feeding for 6 weeks compared to mice not exposed to cholestasis in utero. Female littermates were susceptible to metabolic disease prior to dietary challenge, as indicated by a pro-inflammatory profile, mild hepatosteatosis and elevated serum adipocytokines. In human and mouse placentas, we demonstrated that gestational cholestasis causes accumulation of lipids. We showed increased transplacental cholesterol transport and de novo fetal hepatic lipid synthesis in cholestatic pregnancy. Furthermore, maternal cholestasis in the Agouti viable yellow (Avy) mouse model altered the epigenome of the offspring.
This is the first report showing that maternal cholestasis in the absence of altered maternal BMI or diabetes can cause metabolic disease in the offspring. We have demonstrated that the offspring phenotype is programmed by epigenetic alterations and also impaired lipid transport as a consequence of maternal hypercholanaemia.
Declaration of funding
Genesis Research Trust, Imperial College London, P21764.
Biomedical Research Centre, Imperial College Healthcare NHS Trust
Wellcome Trust, P30874.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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