A multi-omics analysis reveals that the lysine deacetylase ABHD14B influences glucose metabolism in mammals

Abstract

The sirtuins and histone deacetylases are the best characterized members of the lysine deacetylase (KDAC) enzyme family. Recently, we annotated the "orphan" enzyme ABHD14B (α/β-hydrolase domain containing protein # 14B) as a novel KDAC and showed this enzyme's ability to transfer an acetyl-group from protein lysine residue(s) to coenzyme-A to yield acetyl-coenzyme-A, thereby, expanding the repertoire of this enzyme family. However, the role of ABHD14B in metabolic processes is not fully elucidated. Here, we investigated the role of this enzyme using mammalian cell knockdowns in a combined transcriptomics and metabolomics analysis. We found from these complementary experiments in vivo that the loss of ABHD14B results in significantly altered glucose metabolism, specifically the decreased flux of glucose through glycolysis and the citric acid cycle. Further, we show that depleting hepatic ABHD14B in mice also results in defective systemic glucose metabolism, particularly during fasting. Taken together, our findings illuminate the important metabolic functions that the KDAC ABHD14B plays in mammalian physiology and poses new questions regarding the role of this hitherto cryptic metabolism-regulating enzyme.