Research Programme

Research in the Laboratory of Pediatrics is focussed on the (patho) physiology of fat, cholesterol and carbohydrate metabolism, in particular at intestinal and hepatic level

Specific fields of interest:

• Regulation (molecular) of membrane transport of organic and anorganic compounds in liver and intestine.
• Transport of lipids in the body.
• Regulation (molecular) and quantification of metabolic pathways. 

The patterns of energy intake and expenditure in the human body do not parallel each other during the day, illustrating the body's ability to direct substrate flow into and out of energy stores according to its metabolic needs. This is achieved by a finely-tuned regulatory system, operational both on a short-term and a long-term basis, that is controlled to a large extent by the actions of hormones and other signal molecules on activities of enzymes and transporters in their target organs. Although the 'energy content' of diets is often discussed as though carbohydrate and fat were an interchangeable currency, there is now ample evidence that both major energy sources are in fact not interconvertible in the human body.

Yet, there are many, physiologically important, interactions between carbohydrate and fat metabolism that, depending on the supply of these substrates and the prevailing hormonal milieu, govern cellular metabolism. Disturbances of these interactions caused by inborn errors or acquired (e.g., drug-induced) defects leading to deficiencies of certain enzymes, transporters or receptors can have deleterious effects on the body's ability to maintain energy metabolism that are sometimes incompatible with life if not adequately treated. In addition, however, relatively small alterations in the metabolic balance, for instance those induced by (excessive) intake of certain food components, provide the basis for life-style related chronic diseases like diabetes and atherosclerosis.

In particular in these latter cases, further interactions between carbohydrate/fat metabolism on the one hand and that of other physiologically important substances (e.g., cholesterol) on the other hand, are of crucial importance. Resistance against development of these nutrition-related diseases later in life, probably related to an individual's genetic make-up, may be dependent on factors such as intrauterine development and feeding behaviour early in life.

From a metabolic point of view, liver and intestine are the organs that contribute most to the maintenance of homeostasis with respect to carbohydrates, fat and cholesterol. Consequently, issues that are and further need to be addressed concern to a large extent processes that are localized to these organs. The molecular basis of many of the interactions depicted above are currently being unraveled, making use of novel techniques including those of gene transfer and knock-out. This approach has yielded important new information, in particular about nutritional and pharmacological modulation of gene expression and the role of the expanding number of transcription factors herein.

Yet, it should be realized that full appreciation of the physiological consequences of an isolated perturbation of a single step critically depends on accurate measurement of relevant metabolic substrate flows in the in vivo situation. In addition, in view of the very marked species differences that exist between humans and most of the experimental animal models, final proof of the relevance of a specific metabolic alteration requires its evaluation in man itself.

To develop an optimal understanding of "the" system, an integrated approach that involves molecular, cell biological and in vivo evaluation, the latter both in (transgenic) animal models and in humans, is required. Execution of meaningful human experiments has become feasible by the recent introduction of novel mass spectrometric techniques in combination with innovative stable isotope procedures . Such a combination of experimental approaches will ultimately lead to a grade of understanding that allows for development of treatment and/or prevention strategies for specific disorders on a scientific basis.

 

 

• Obviously, there are multiple interactions between these lines and researchers are involved in multiple lines. In addition, intensive collaborations with the Laboratory of Gastroenterology and Hepatology have been established.
• This research line is embedded in the program of the "Center for Liver, Digestive and Metabolic Diseases" (coordinated by prof. H.J. Verkade) of the "Graduate School for Drug Exploration (GUIDE)".

 

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