N-Acetylaspartate Accumulation in Enterocytes Governs Intestinal Lipid Absorption.

In obesity and obesity-associated chronic conditions such as type 2 diabetes, the intestine mediates lipid burden by absorbing fats, packing them for transport, and sensing nutrients to signal secretion of incretins. The intestine requires constant replenishment of amphibolic intermediates to support these metabolic demands. However, the enterocyte-specific metabolites responsible for meeting the energetic demands for hormone secretion and nutrient absorption remain mostly unknown. I found that a modified and brain-enriched amino acid, N-acetylaspartate (NAA), and its hydrolysis enzyme, Aspartoacylase (Aspa), are highly abundant and concentrated in the small intestine. Although the NAA-ASPA pathway has not been characterized outside the brain, I found ASPA is highly expressed in the villus region of the mouse and human small intestine and is significantly upregulated during differentiation in human enteroids. Additionally, using a whole body Aspa knockout mouse model (AspaKO), I demonstrated that mice lacking Aspa have shorter villi, indicating reduced surface area for nutrient absorption and a malabsorption phenotype. From these observations, we sought to understand how the addition of a high fat diet (HFD) challenge would impact NAA metabolism in these mice. After 12 weeks on HFD, AspaKO mice had lower body weights, longer intestines, and shorter villi compared to controls. Additionally, these mice showed improved oral glucose tolerance, insulin sensitivity, and lower food intake. Bulk RNA-seq profiling of the ileum from AspaKO on HFD revealed increased expression of the lipid-sensing transcription factor SREBP2 and its target genes associated with de novo cholesterol synthesis. Interestingly, these expression changes occur only in the refed state, not in the fasted state, suggesting a stronger stimulus during the reintroduction of lipids. To further determine if cholesterol is being absorbed by the intestine in AspaKO HFD mice, I measured systemic total cholesterol and saw lower levels along with complete depletion of LDL-C compared to HFD controls. Therefore, our data suggest that NAA accumulation in enterocytes increases SREBF2 during refeeding, further lowering cholesterol absorption. Using the Atherosclerosis Risk in Communities Study (ARIC), we find that NAA levels are inversely associated with obesity. Given that hypercholesterolemia strongly increases the risk of atherosclerosis and cardiovascular disease, my work on NAA reveals new nutrient signaling and mechanisms that govern lipid homeostasis and protection against conditions associated with obesity.

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