22 Chapter 1 mentioned kinetic model. Moreover, I also analyze the effects of the previously described DHA supplement on the pathway to understand the role of this PPAR-α agonist. Part III- Medium Chain Acyl-CoA Dehydrogenase Deficiency Next, in chapter 6 together with my colleague from the Systems Medicine group of the UMCG I develop an iPSC-derived hepatobiliary organoid model to study a particular IEM. In this case, we use fibroblasts-derived iPSCs from healthy and MCAD-deficient children and differentiate them into hepatocyte-like organoids. We show that these organoids recapitulate the biochemical MCADD phenotype and serve as valuable tool to understand pathophysiological aspects of the disease. Finally, once the MCADD organoids have been established and characterized we focus on the study of peroxisomes and the potential role they play in metabolizing medium-chain fatty acids (accumulated in the absence of MCAD) as well as on their role in coenzyme A (CoA) metabolism. Part IV- General Discussion and future perspectives Finally, in chapter 7 I evaluate the progress made in the study of malnutrition and MCAD deficiency with this thesis and the advances it permitted. I focus on the potential and limitations of in vitro models and propose different solutions. I also focus on the interplay of peroxisomes and mitochondria in health and disease and the potential compensatory mechanisms from one organelle to the other. Finally, I discuss the future directions and application of translational models for metabolic research.
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