Fetal and neonatal environment: effects on bile acid and lipid metabolism

PhD ceremony: Ms. H. van Meer, 16.15 uur, Academiegebouw, Broerstraat 5, Groningen

Dissertation: Fetal and neonatal environment: effects on bile acid and lipid metabolism

Promotor(s): prof. H.J. Verkade

Faculty: Medical Sciences

Epidemiological data associate adult disease to factors in the fetal- and early postnatal environment. Maternal gestational under-nutrition affects the offspring’s adult lipid metabolism. This association between fetal environment and adult disease is called “metabolic programming”. Knowledge about the pathophysiological mechanisms of metabolic programming can be relevant to improve long-term health through early preventive nutritional manipulations.

Using stable-isotope-techniques we studied the consequences of, and mechanisms underlying dietary- and pharmacological interventions during prenatal life on the lipid metabolism. In mice, fetal under-nutrition did not affect maternal-fetal cholesterol transport or the biosynthesis of cholesterol or fatty-acids in the last stage of gestation. In human infants, intrauterine-growth-restriction did not substantially affect the synthesis rates of lipids. The Liver-X-Receptor (LXR), an important regulator of lipid metabolism, is active in the fetal liver and can be stimulated pharmacologically by administration of an agonist in the diet of pregnant mice. Pharmacological LXR activation affected lipid metabolism in the fetal offspring in mice, without substantially affecting the lipid metabolism in the offspring in adulthood.

Overall, we showed that our stable-isotope-methodology allows the determination of effects of the maternal environment on the lipid metabolism in the murine fetus and in small infants. Our results indicate that fetal malnutrition does not lead to profound adaptations in the fetal lipid metabolism. Adaptations in fetal lipid metabolism, initiated by pharmacological LXR activation, do not sustain into adulthood. These findings do not support the hypothesis that effects of the fetal environment on adult lipid metabolism are mediated by adaptations in the fetal lipid metabolism.