N-acetylaspartate Pathway Is Nutrient Responsive and Coordinates Lipid and Energy Metabolism in Brown Adipocytes
Katharina Huber, Dina C Hofer, Sophie Trefely, Helmut J Pelzmann, Corina Madreiter-Sokolowski, Madalina Duta-Mare, Stefanie Schlager, Gert Trausinger, Sarah Stryeck, Wolfgang F Graier, Dagmar Kolb, Christoph Magnes, Nathaniel W Snyder, Andreas Prokesch, Dagmar Kratky, Tobias Madl, Kathryn E Wellen, Juliane G Bogner-Strauss
Biochimica et biophysica acta. Molecular Cell research , 3/2019
The discovery of significant amounts of metabolically active brown adipose tissue (BAT) in adult humans renders it a promising target for anti-obesity therapies by inducing weight loss through increased energy expenditure. The components of the N-acetylaspartate (NAA) pathway are highly abundant in BAT. Aspartate N-acetyltransferase (Asp-NAT, encoded by Nat8l) synthesizes NAA from acetyl-CoA and aspartate and increases energy expenditure in brown adipocytes. However, the exact mechanism how the NAA pathway contributes to accelerated mobilization and oxidation of lipids and the physiological regulation of the NAA pathway remained elusive. Here, we demonstrate that the expression of NAA pathway genes corresponds to nutrient availability and specifically responds to changes in exogenous glucose. NAA is preferentially produced from glucose-derived acetyl-CoA and aspartate and its concentration increases during adipogenesis. Overexpression of Nat8l drains glucose-derived acetyl-CoA into the NAA pool at the expense of cellular lipids and certain amino acids. Mechanistically, we elucidated that a combined activation of neutral and lysosomal (acid) lipolysis is responsible for the increased lipid degradation. Specifically, translocation of the transcription factor EB to the nucleus activates the biosynthesis of autophagosomes and lysosomes. Lipid degradation within lysosomes accompanied by adipose triglyceride lipase-mediated lipolysis delivers fatty acids for the support of elevated mitochondrial respiration. Together, our data suggest a crucial role of the NAA pathway in energy metabolism and metabolic adaptation in BAT.
Keywords: Asp-NAT; Aspartoacylase; Brown adipocytes; Energy expenditure; Fatty acid metabolism; Lipid metabolism; Lipophagy; N-acetylaspartate; N-acetyltransferase 8-like