Exposure to complement induced preeclampsia promotes fetal steatosis

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Abstract: Now it is well recognized that exposure to adverse intrauterine environment can greatly affect the health postnatally and in adulthood. Exposure to maternal obesity during gestation is linked to offspring adiposity, premature mortality from cardiovascular disease and hepatic steatosis in humans. Evidence from different experimental animal models including rodents and non-human primates strongly suggests that exposure to maternal overnutrition during gestation promotes fetal hepatic fat storage (steatosis) with a long-lasting metabolic consequence for offspring. In contrast to steatosis in adults where increased hepatic de novo lipogenesis and decreased fatty acid oxidation are observed, steatosis in fetuses exposed to maternal obesity is predominantly due to increased transplacental fuel transfer since increased de novo lipogenesis is not observed in them. Increased hepatic de novo cholesterol synthesis and its decreased clearance were also observed in adult NAFLD/NASH. Regardless of the source of lipids, obesity associated steatosis in both prenatal and adults is characterized by overwhelming hepatic lipid load surpassing hepatocyte lipid metabolic contingency. In contrast to nutrition rich intrauterine environment of maternal obesity, PE is often associated with reduced nutritional supply to the developing fetus and consequent intrauterine growth restriction (IUGR). Prevalence of NAFLD is about 4 times higher in children after IUGR compared to those with normal birth weight. Adulthood NAFLD is independent of childhood body mass index and insulin secretion ruling out catch-up growth as the sole reason for NAFLD. The mechanism linking IUGR to adulthood NAFLD is not known. Under normal physiological conditions two important sources for liver lipids including cholesterol are de novo synthesis and receptor mediated import from blood circulation. Since liver is not a lipid storage depot, liver lipids are utilized in β-oxidation or secreted out mainly as very low-density lipoproteins (VLDL). Cholesterol is an obligate component of VLDL and required for VLDL secretion from the liver. Based on these observations we hypothesize that in IUGR fetuses steatosis occurs due to increased import of lipids accompanied by the deficiency of cholesterol and impaired VLDL secretion. Fetal liver steatosis could prime the liver for later liver metabolic diseases through similar mechanisms as involved in maternal obesity associated adulthood NAFLD. In this application we propose to understand fetal liver lipid metabolism under IUGR using a novel PE mouse model we recently developed in our laboratory.