219 A Summary In this thesis, I have focused on the establishment of in vitro and in silico models for the study of two diseases affecting fatty acid metabolism. The first disease, central to this thesis, is severe malnutrition. Malnutrition refers to an imbalance or deficit in the intake of energy and/or nutrients necessary to maintain cellular homeostasis. Malnutrition can be caused by a deficiency or excess of nutrients, undernutrition and overnutrition respectively. In this thesis the term malnutrition is used to refer to undernutrition. Severe malnutrition is known as the most severe form of macronutrient deficiency, such as that of proteins or lipids. Long exposures to low protein diets result in low number of peroxisomes in the liver. Peroxisomes are small, singlemembrane organelles, present in most eukaryotic cells, with a wide range of functions including metabolism of fatty acids (long, very-long, and branchedchain fatty acids). In the case of children, severe malnutrition hinders optimal growth and development. Current approaches for the study of malnutrition are primarily based on the use of animal models, including primates, rats, and most frequently, mice on low protein diets (LPD). These models have proven extremely valuable to understand the pathophysiology of malnutrition in the liver and intestine and are able to recapitulate specific disease phenotypes (e.g., hepatic steatosis or barrier dysfunction). Moreover, they allow for a whole-body characterization and study of the interplay between the organs. Although physiologically relevant, they are also limited by blood and tissue sampling, the large numbers of animals required per study and translational discrepancies between humans and rodents. The second disease discussed in this thesis is medium chain acyl-CoA dehydrogenase deficiency (MCADD). Medium chain acyl-CoA dehydrogenase (MCAD) is a mitochondrial enzyme in charge of metabolizing medium chain fatty acids. MCADD is a genetic disorder that affects the body's ability to process medium-chain fatty acids. This can lead to energy deficits during fasting, long bouts of exercise or intercurrent illness. In the case of MCADD, mitochondria (a subcellular organelle with a central role in the Gibbs energy supply to the cell) are affected. While the effects of malnutrition on peroxisomes have been widely described, little is known about the effects of MCADD on said organelle. Similar to the first disease, conventional approaches for the study of MCADD involve the use of animal models in which the disease is induced. One very important limitation of rodent models for MCADD is the presence of an extra enzyme (with similar functions to MCAD) not present in humans.
RkJQdWJsaXNoZXIy MTk4NDMw