SAT-657 N-acetylaspartate accumulation in the liver decreases lipogenesis

Abstract Disclosure: P. Patel: None. E. de Groot: None. P. Saha: None. S.M. Hartig: None. N-acetylaspartate (NAA) is the second most abundant metabolite in the brain, and the metabolites generated from its catabolism direct the myelination of nerves. Despite abundant circulating NAA, roles outside the brain remain unknown. The hydrolysis of NAA by the enzyme aspartoacylase (ASPA) leads to the generation of acetate and aspartate, supplying rate-limiting metabolites for essential cellular processes, including lipogenesis. Lipogenesis occurs in the liver to store excess carbohydrates in times of nutrient overload. However, excessive fat accumulation in the liver can lead to fatty liver disease. Interestingly, we found that Aspa expression and NAA abundance are decreased in the livers of mice placed on a high-fat diet. To better understand NAA’s function in the liver, we utilized a whole-body ASPA knockout (KO) mouse model that accure NAA. As such, we find that ASPA KO mice are resistant to fatty liver. ASPA KO livers were larger when normalized to body weight, accumulated less triglycerides, and expressed lower levels of key lipogenic genes relative to age-matched littermate controls. These mice also had increased serum free fatty acids that do not appear in the liver. As an alternative method to increase NAA levels in the liver, we overexpressed N-acetylaspartate synthetase (Nat8l), the enzyme that synthesizes NAA from acetate and aspartate. Consistent with our findings in the ASPA-deficient mice, Nat8l overexpression in the liver resulted in decreased liver triglycerides. In parallel, we find that per orem NAA in wild-type (WT) mice decreases cytidine diphosphate (CDP) and glyceraldehyde 3-phosphate (G3P), both of which contribute to lipid synthesis in the liver. From these data, we can hypothesize that NAA provides an acetate pool for lipogenesis, and the presence of ASPA determines whether the liver can accumulate pathological amounts of fat. Presentation: Saturday, July 12, 2025