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

Abstract

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.

Keywords: GABA(A) receptor; GPCR; acyl-CoA; acyl-CoA binding protein (ACBP); diazepam binding inhibitor (DBI); fatty acid metabolism.

Figure 1. Tertiary structure of holo DBI/ACBP (bovine) with bound palmitoyl-CoA.

The peptide backbone is depicted in grey (PDB 1NVL), while the acyl-group and CoA of palmitoyl-CoA are shown in green and yellow, respectively. Two peptides that can be derived from ACBP/DBI, ODN (ACBP/DBI_33–50) and TTN (ACBP/DBI_17–50), are shown in light blue and blue, respectively. In the lower panel sequences of ACBP/DBI from human, mouse, bovine and goldfish have been aligned and sequences covering ODN and TTN shown.

Figure 2. Selected intracellular functions of ACBP/DBI.

ACBP/DBI (illustrated as a light green Pacman shape) can act as an acyl-CoA pool former, protecting long-chain acyl-CoA esters (LCACoAs) from hydrolysis by thioesterases (TES), extract LCACoAs from membranes, deliver LCACoAs to glycerolipid, glycerophospholipid, and ceramide synthesis (CerS), to fatty acid elongation by fatty acid elongases (ELOVL) and to mitochondrial β-oxidation. ACBP/DBI also relieves inhibition of the enzymes FAS, ACC and ACS by LCACoAs. Abbreviations: ACAT, acyl-CoA:cholesterol acyltransferase; ACC, acyl-CoA carboxylase; ACSL, acyl-CoA synthetase; AGPAT, acylglycerol-3-phosphate-acyltransferase; Cer, ceramide; CerS, ceramide synthase; CPT1, carnitine palmitoyltransferase 1; dhSph, dihydrosphingosine; dhCer, dihydroceramide; ELOVL, elongation of very long chain fatty acids; FAS, fatty acid synthase; GPAT, glycerol-3-phosphat acyltransferase; LIPN-1, Lipin-1; SPTLC1, Serine Palmitoyltransferase Long Chain Base Subunit 1.

Figure 3. Pleiotropic roles of ACBP/DBI as a secreted extracellular (in blue) and intracellular (in red) protein on peripheral lipid metabolism, hormone secretion and brain functions.

In most cells, intracellular ACBP plays a key role in intracellular fatty acid fluxes and metabolism including LCFACoA oxidation and esterification in neural and tumor cells as well as lipogenesis in fat and liver cells. In the skin, ACBP promotes ceramide and very-long chain fatty acid synthesis which is essential to maintain the trans-epidermal barrier and energy homeostasis. In the brain, secreted ACBP promotes neurogenesis and neuroprotection via GABA_AR and ODN-GPCR-dependent pathways respectively. In addition, extracellular ACBP modulates synaptic transmission, neural function, and diverse types of behavior including feeding behavior. Circulating ACBP levels are affected by changes in the metabolic status and fat mass. Extracellular ACBP regulates hormone secretion in the gut (CCK) and endocrine pancreas (insulin) as well as lipid metabolism in adipocytes. Peripheral administration of ACBP promotes feeding and anabolic pathways (lipogenesis in liver and fat cells) though it remains unclear whether the effects of exogenous ACBP on metabolism and food intake are direct (via GABA_AR and/or ODN-GPCR) and/or indirect (via hormone secretion and/or afferent neurons).