From benzodiazepines to fatty acids and beyond: revisiting the role of ACBP/DBI.

Four decades ago Costa and colleagues identified a small, secreted polypeptide in the brain that can displace the benzodiazepine diazepam from the GABA A receptor, and was thus termed diazepam binding inhibitor (DBI). Shortly after, an identical polypeptide was identified in liver by its ability to induce termination of fatty acid synthesis, and was named acyl-CoA binding protein (ACBP). Since then, ACBP/DBI has been studied in parallel without a clear and integrated understanding of its dual roles. The first genetic loss-of-function models have revived the field, allowing targeted approaches to better understand the physiological roles of ACBP/DBI in vivo. We discuss the roles of ACBP/DBI in central and tissue-specific functions in mammals, with an emphasis on metabolism and mechanisms of action. DBI was identified on its ability to displace diazepam from the benzodiazepine binding site on GABA A receptors. ACBP was identified on its ability to induce termination of fatty acid synthesis in goat mammary gland. ACBP/DBI binds long-chain fatty acyl-CoA esters (LCACoAs) with very high affinity. DBI/ACBP is secreted by the unconventional secretory pathway and can be cleaved to regulatory signaling peptides including triakontatetraneuropeptide (ACBP/DBI 1 7– 50) and octadecaneuropeptide (ACBP/DBI 3 3– 50). As an extracellular protein, ACBP/DBI and its derived peptides have pleiotropic effects on gut and pancreatic hormone secretion, neurogenesis, neuronal survival, cognition, and behavior, as well as on energy balance neurocircuits. As an intracellular protein, ACBP/DBI sequesters LCACoAs and mediates their flux to enzymes including ceramide synthases. ACBP/DBI relieves LCACoA-mediated inhibition of enzymes such as acetyl-CoA carboxylase and acyl-CoA synthetases. [ABSTRACT FROM AUTHOR]