Acss2 Deletion Reveals Functional Versatility via Tissue-Specific Roles in Transcriptional Regulation

The coordination of cellular biological processes is regulated in part via metabolic enzymes acting to match cellular metabolism to current conditions. The acetate activating enzyme, acyl-coenzyme A synthetase short-chain family member 2 (Acss2), has long been considered to have a predominantly lipogenic function. More recent evidence suggests that this enzyme has regulatory functions in addition to its role in providing acetyl-CoA for lipid synthesis. We used Acss2 knockout mice (Acss2(-/-)) to further investigate the roles this enzyme plays in three physiologically distinct organ systems that make extensive use of lipid synthesis and storage, including the liver, brain, and adipose tissue. We examined the resulting transcriptomic changes resulting from Acss2 deletion and assessed these changes in relation to fatty acid constitution. We find that loss of Acss2 leads to dysregulation of numerous canonical signaling pathways, upstream transcriptional regulatory molecules, cellular processes, and biological functions, which were distinct in the liver, brain, and mesenteric adipose tissues. The detected organ-specific transcriptional regulatory patterns reflect the complementary functional roles of these organ systems within the context of systemic physiology. While alterations in transcriptional states were evident, the loss of Acss2 resulted in few changes in fatty acid constitution in all three organ systems. Overall, we demonstrate that Acss2 loss institutes organ-specific transcriptional regulatory patterns reflecting the complementary functional roles of these organ systems. Collectively, these findings provide further confirmation that Acss2 regulates key transcription factors and pathways under well-fed, non-stressed conditions and acts as a transcriptional regulatory enzyme.

Automated summary

The acetate activating enzyme Acss2 plays a role in matching cellular metabolism to current conditions and has regulatory functions in addition to its role in lipid synthesis. Using Acss2 knockout mice, this study investigated the roles of Acss2 in liver, brain, and adipose tissue and found dysregulation of numerous signaling pathways and cellular processes. The loss of Acss2 resulted in few changes in fatty acid constitution in these organ systems. Overall, this research demonstrates the organ-specific transcriptional regulatory patterns of Acss2 and its role as a regulatory enzyme.