Impact du stress oxydant et de l'inflammation sur le métabolisme intestinal des lipides et les fonctions mitochondriales dans la fibrose kystique
Cystic fibrosis (CF) is a lethal monogenic disease that predominantly affects Caucasians. It results from the mutation of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene. The deficiency in essential fatty acids (EFA) is classical and is associated with intestinal lipid and liposoluble vitamin malabsorption that is extremely difficult to control. Oxidative stress (OxS) and inflammation could participate in the occurrence of these lipid disorders by involving the mitochondria, a key organelle of redox homeostasis. The hypothesis of this work is that the deletion in the CFTR gene is associated with oxidative, inflammatory and mitochondrial perturbations, and alters intestinal lipid metabolism in CF. The specific objectives are to characterize the oxidative and inflammatory profile, to evaluate the functioning of mitochondria and to identify the modulation of lipid metabolism in the intestine. The CFTR gene deletion in Caco-2/15 intestinal epithelial cells was performed using the innovative Zinc Finger Nuclease transfection method, which allowed the generation of a CFTR (-/-) knockout cell line. Our results demonstrate the presence of an oxidative and inflammatory profile related to CFTR deficiency. Mitochondrial dysfunctions such as DNA oxidative damage, energy metabolism derangement and susceptibility to apoptosis are probably the result of the downregulation of PGC1α and NRF2 transcription factors, as they represent the dominant regulators of mitochondrial biogenesis and transcription of antioxidant response elements. The lipid profile is in favor of exaggerated lipogenesis, increased lipid synthesis and lipoprotein overproduction. These results underline mitochondrial dysfunction arising solely from the CFTR gene defect but, on the other hand, they suggest that the typical lipid transport abnormalities of CF patients result from the entanglement of various factors such as mucus abnormalities, morphological aberrations in the intestinal epithelium, exocrine pancreatic insufficiency and irregular liver bile acid metabolism.
Inflammation intestin Oxidative Stress Intestine Mitochondria Lipids Cystic Fibrosis