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Characterization of the sex specific metabolic phenotype in very-long chain acyl-CoA dehydrogenase deficient (VLCAD-/-) mice

Subject Area Gastroenterology
Term from 2018 to 2023
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 410964249
 
Final Report Year 2023

Final Report Abstract

Mitochondria supply the cells with up to 90% of the energy in the form of ATP. One of the most important process is represented by the mitochondrial β-oxidation of long-chain fatty acids. Deficiencies in one or more enzymes involved in this pathway belong to the group of diseases known as fatty acid oxidation disorders (FAOD), rare autosomal recessive diseases included in newborn screening programs of many countries worldwide. Episodes of acute metabolic decompensation may lead to threathening events, coma and death. One of this diseases is represented by the very long-chain acyl-CoA dehydrogenase deficiency (VLCADD). Treatment recommendations include avoidance of fasting, restriction of dietary long-chain fatty acids and supplementation with carbohydrates and medium-even-chain fatty acids (MCT oil) as this can be fully metabolized supplying the organism with the required energy. Although considered safe, VLCAD-/- mice fed long-term with an MCT-based diet developed a severe metabolic syndrome in a sex-specific manner. Within this project, we performed a comprehensive metabolic phenotyping, SILAC- based quantitative proteomics and characterized the involved signalling pathways by western blot analysis and gene expression. WT and VLCAD-/- mice showed strong sex-dependent differences in basal metabolism and expression of proteins involved in the distinct metabolic pathways, even more prominent after treatment with MCT. The investigation of molecular mechanisms responsible for the sexual dimorphisms delineated the selective activation of the ERK/mTORc1 signaling pathway leading to an increased biosynthesis and elongation of fatty acids in VLCAD-/- females. In contrast, MCT induced the activation of ERK/PPARγ pathway and the subsequent upregulation of peroxisomal β-oxidation in males. This sexual dimorphism was also reflected in the content and composition of the complex lipids exacerbated by the incubation with MCT. Shotgun lipidomic analysis followed by SILAC-based proteomics confirmed that although MCT led to the stimulation of lipogenesis in both sexes, the outcome was completely different. Fibroblasts from VLCAD-/- female mice on MCT accumulated phosphatidylcholine (PC) and lyso-PC strongly suggestive of a sex dependent proinflammatory effect. In contrast, the MCT-induced stimulation of peroxisomal activity described in cells from VLCAD-/- male mice was reflected in the accumulation of plasmalogens and neutral lipids. Despite the remarkable differences observed between the sexes, the biological and physiological implications of alterations in the composition of membrane phospholipids are rather complex and difficult to translate to humans. In this regard, taking advantage of a multi „omics“ approach on fibroblasts from different long-chain FAOD, we demonstrated a disease-specific lipid signature accompanied by proteomic alteration responsible for the onset of the described clinical phenotype.

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