Programming of lipid metabolism

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Human and animal studies indicate that the nutritional status of the mother during pregnancy affects long-term health of the offspring. This process, in which early adaptations to specific nutritional conditions permanently change the physiology and metabolism of the organism and continue to be expressed even in the absence of the condition that initiated them, is termed "metabolic programming". The molecular mechanisms of metabolic programming are largely unknown. The aim of the research described in this thesis was to unravel molecular mechanisms and physiological consequences of metabolic programming. We have chosen to obtain metabolic programming by pharmacologically or nutritionally influencing the status of the mother during gestation.
The mechanisms by which fetal and early postnatal environment influence lipid homeostasis in adult life are poorly defined. One of the key players in (adult) cholesterol and lipid metabolism is the Liver X Receptor. LXR alpha and beta have been shown to be crucially involved in the regulation of cellular cholesterol homeostasis in adult mammals, namely in the liver, the intestine and in macrophages. In short, the LXRs are activated by oxysterols (oxidized cholesterol derivatives), bind to their heterodimer partner Retinoid X-Receptor (RXR) and activate transcription of their target genes. Important LXR targets are ATP-binding cassette (ABC) transporters involved in cholesterol efflux from cells to the intestinal lumen or bile (ABCG5/ABCG8), or to highdensity lipoproteins (HDL) (ABCAl, ABCG1). Moreover, the LXRs activate transcription of genes responsible for de novo lipogenesis (SREBP1C, FASN) which provides a mean to detoxify cholesterol by the formation of cholesterylesters

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