PUTATIVE FUNCTIONS OF THE LIPOGENIC ENZYME ASPARTOACYLASE IN THE INTESTINE

ABSTRACT Epithelial cells of the intestine perform metabolic reactions to sustain energy requirements for supporting gut peptide secretion from hormone-producing enteroendocrine cells, carbohydrate and amino acid absorption by enterocytes, lipid synthesis and storage, and cell turnover. Acetate, a precursor to acetyl-CoA, is an essential intermediate metabolite driving vital cellular processes, including the TCA cycle and de novo lipogenesis. Acetate can be generated from N-acetylaspartate (NAA), an essential brain metabolite for myelin lipids. The only enzyme capable of cleaving NAA is aspartoacylase (ASPA), which generates acetate and aspartate. Although the importance of NAA breakdown and ASPA is known in the brain, its function in other tissues is unknown. I found that Aspa is highly expressed in the mid-villus enterocytes in the small intestine. I also demonstrated that inducible whole-body knockout of Aspa in mice increases insulinotropic hormones after glucose administration and that their ileum tissue harbors less aspartic acid. These observations, coupled with other literature, suggest that ASPA expression contributes to the endocrine functions of the intestine and furnishes metabolites derived from NAA within absorptive enterocytes. The goal of this proposal is to identify the fate of NAA-derived acetate and aspartate in cells of the small intestine by understanding how altered ASPA expression affects hormone secretion, enterocyte carbohydrate and lipid absorption, and cell turnover. To pursue this goal and to enhance my training in intestine biology and metabolism, I designed two Aims. In Aim 1, I will define how Aspa deficiency impacts gut hormones and nutrient metabolism using an intestine-specific Aspa knockout mouse model. In Aim 2, I will use intestine organoids to define how NAA hydrolysis contributes to intracellular pools of acetate and aspartate. Completing this project will identify the novel function of ASPA and NAA in the intestine, identifying insights into potential new cellular and metabolic functions of enterocytes and energy-carrying metabolites, which are potential contributors to metabolic dysfunctions in digestive diseases.