Acetyl-CoA mediated autoacetylation of fatty acid synthase in de novo lipogenesis

SUMMARY De novo lipogenesis (DNL) is a highly regulated metabolic process, which is known to be activated through transcriptional regulation of lipogenic genes, including fatty acid synthase (FASN). Unexpectedly, we find that the expression of FASN protein remains unchanged during Drosophila larval development when lipogenesis is hyperactive. Instead, acetylation modification of FASN is highly upregulated in fast-growing larvae. We further show that lysine K813 is highly acetylated in developing larvae, and its acetylation is required for upregulated FASN activity, body fat accumulation, and normal development. Intriguingly, K813 is rapidly autoacetylated by acetyl-CoA in a dosage-dependent manner, independent of known acetyltransferases. Furthermore, the autoacetylation of K813 is mediated by a conserved P-loop-like motif (N-xx-G-x-A). In summary, this work uncovers a novel role of acetyl-CoA-mediated autoacetylation of FASN in developmental lipogenesis and reveals a self-regulatory system that controls metabolic homeostasis by linking acetyl-CoA, lysine acetylation, and DNL. Graphical Abstract:biorxiv;2022.01.06.475252v1/UFIG1F1ufig1 Highlights:Acetylation modification of FASN, but not protein expression, positively correlates with de novo lipogenesis during Drosophila larval developmentSite-specific acetylation at K813 residue enhances FASN enzymatic activityK813 residue is autoacetylated by acetyl-CoA, independent of KATsA novel N-xx-G-x-A motif is required for autoacetylation of K813