Towards investigating apolipoprotein E genotypes on the metabolism of long chain fatty acids

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Long-chain polyunsaturated fatty acids (LC-PUFA) are provided almost exclusively by the diet. They are important to maintain the physical nature of cell membranes and induce gene expression or repression in many different cell types. LC-PUFA are mainly delivered to organs by circulating lipoproteins that contains apolipoprotein E (APOE) protein. There are three existing isoforms of this protein in human namely APOE2, APOE3 and APOE4. We have recently shown in humans carriers of APOE4 that there are imbalances in the distribution of LC-PUFA in plasma total lipids. These imbalances potentially deregulate the cellular content in LC-PUFA and hence induce dysfunctions in gene expression or repression. Since APOE is expressed in many different types of cells, transgenic mice knock-in for human APOE genotypes provide unique tools to study the cellular source-dependant role of APOE isoforms in LC-PUFA homeostasis. Therefore, our objective is to elucidate the role(s) of APOE genotypes on LC-PUFA metabolism and gene expression or repression. To do so, we will use transgenic mice carrying human APOE2, APOE3 or APOE4 genotype. In our first experiment, we will use three carbon 13 non-radioactive fatty acids (tracers) to monitor precisely the metabolism of these fatty acids over one month. In our second experiment, we will feed the mice one of the four following diets: A) a control diet, B) a diet enriched in omega-3 LC-PUFA, C) a diet deprived in omega-3 LC-PUFA and other omega-3 fatty acids and D) a high-fat diet that will produce human-like lipoprotein levels. Because these diets will change the cellular content of organs such as liver, heart and white adipose tissue, we will quantify the cellular content in LC-PUFA and quantify the expression of fatty acid transporters and fatty acid receptor genes and quantify their respective protein levels. This work will contribute to better understand how one specific gene-by-diet interaction (LC-PUFA by APOE genotypes) change the whole body homeostasis in LC-PUFA. This is an important question to investigate considering the regulatory role of LC-PUFA in the cells.