Maternal cholestasis during pregnancy programs metabolic disease in offspring.
The intrauterine environment is a major contributor to increased rates of metabolic disease in adults. Intrahepatic cholestasis of pregnancy (ICP) is a liver disease of pregnancy that affects 0.5%-2% of pregnant women and is characterized by increased bile acid levels in the maternal serum. The influence of ICP on the metabolic health of offspring is unknown. We analyzed the Northern Finland birth cohort 1985-1986 database and found that 16-year-old children of mothers with ICP had altered lipid profiles. Males had increased BMI, and females exhibited increased waist and hip girth compared with the offspring of uncomplicated pregnancies. We further investigated the effect of maternal cholestasis on the metabolism of adult offspring in the mouse. Females from cholestatic mothers developed a severe obese, diabetic phenotype with hepatosteatosis following a Western diet, whereas matched mice not exposed to cholestasis in utero did not. Female littermates were susceptible to metabolic disease before dietary challenge. Human and mouse studies showed an accumulation of lipids in the fetoplacental unit and increased transplacental cholesterol transport in cholestatic pregnancy. We believe this is the first report showing that cholestatic pregnancy in the absence of altered maternal BMI or diabetes can program metabolic disease in the offspring.
Institute of Reproductive and Developmental Biology, Hammersmith Hospital, Imperial College London, London, United Kingdom.
Georgia
G
Papacleovoulou
Shadi
S
Abu-Hayyeh
Evanthia
E
Nikolopoulou
Oscar
O
Briz
Bryn M
BM
Owen
Vanya
V
Nikolova
Caroline
C
Ovadia
Xiao
X
Huang
Marja
M
Vaarasmaki
Marc
M
Baumann
Eugene
E
Jansen
Christiane
C
Albrecht
Marjo-Riitta
MR
Jarvelin
Jose J G
JJ
Marin
A S
AS
Knisely
Catherine
C
Williamson
D052436:Adipose Tissue, White / Q000378:metabolism; D000293:Adolescent; D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D001786:Blood Glucose; D016022:Case-Control Studies; D002478:Cells, Cultured; D002780:Cholestasis, Intrahepatic / Q000150:complications* / Q000378:metabolism; D004032:Diet; D004198:Disease Susceptibility / Q000209:etiology / Q000378:metabolism; D044127:Epigenesis, Genetic; D005234:Fatty Liver / Q000209:etiology* / Q000378:metabolism; D005260:Female; D006706:Homeostasis; D006801:Humans; D007328:Insulin / Q000097:blood; D050356:Lipid Metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000209:etiology* / Q000378:metabolism; D010920:Placenta / Q000378:metabolism; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism; D011297:Prenatal Exposure Delayed Effects / Q000209:etiology* / Q000378:metabolism; D039401:Prenatal Nutritional Physiological Phenomena; D059467:Transcriptome
D001647:Bile Acids and Salts; D001786:Blood Glucose; D007328:Insulin