SUN-677 Putative Functions of the Lipogenic Enzyme Aspartoacylase in the Intestine

Abstract Disclosure: E. de Groot: None. P.K. Saha: None. M. Herman: None. J. Mills: None. S.M. Hartig: None. The intestine requires constant replenishment of energy-carrying intermediates to support the metabolic demands of rapid intestinal cell turnover, nutrient absorption, and hormone secretion in the villus epithelium. However, the metabolites fueling energy pools for intestinal absorption and endocrine functions remain poorly characterized. Acetate, along with glucose and fatty acids, is an essential metabolic intermediate that provides carbon for acetyl-CoA to serve essential energy metabolism pathways and histone acetylation. Acetate can also be generated from N-acetylaspartate (NAA), an abundant and critical brain metabolite for myelin lipids. The only enzyme capable of cleaving NAA is aspartoacylase (ASPA), which generates acetate and aspartate. Although the role of NAA breakdown by ASPA is well-established in the brain, its function in other tissues is unknown. We found that Aspa is highly expressed in the mid-villus absorptive enterocytes in the small intestine. Contrary to other tissues, the enzyme responsible for generating NAA, NAT8L, is not expressed along the digestive tract. To nominate functions of ASPA, we generated tamoxifen-inducible whole-body Aspa knockouts (AspacKO), obviating developmental phenotypes observed in germline knockouts. We then performed untargeted metabolomics to broadly assess metabolite changes among knockouts and controls. As such, we found reduced aspartic acid in the ileum, suggesting that Aspa deletion lowers the availability of NAA hydrolysis products. Oral glucose tolerance tests showed AspacKO exhibit greater glucose disposal and higher plasma levels of glucose-dependent insulinotropic polypeptide (GIP) and insulin. As Aspa is not expressed in any endocrine cells of the pancreas, this suggests that intestinal ASPA expression supports gut hormone responses to carbohydrates and lipids. Our preliminary analysis of ASPA expression in vivo and in vitro reveals an unknown and important role for NAA in metabolic influence of the incretin axis and cellular acetate and aspartate supply. This research addresses intestine-specific roles for ASPA and NAA that have never been previously defined. Further research will nominate novel NAA-ASPA pathways and aid in understanding how metabolic and digestive diseases alter gut epithelial homeostasis and nutrient absorption in ways that can influence physiology. Presentation: Sunday, July 13, 2025