Inhibition of acyl-CoA binding protein (ACBP) by means of a GABAARγ2-derived peptide

Author:

Anagnostopoulos GerasimosORCID,Saavedra Ester,Lambertucci Flavia,Motiño OmarORCID,Dimitrov JordanORCID,Roiz-Valle David,Quesada Victor,Alvarez-Valadez Karla,Chen Hui,Sauvat AllanORCID,Rong Yan,Nogueira-Recalde Uxía,Li Sijing,Montégut Léa,Djavaheri-Mergny Mojgan,Castedo Maria,Lopez-Otin Carlos,Maiuri Maria ChiaraORCID,Martins IsabelleORCID,Kroemer GuidoORCID

Abstract

AbstractAcyl-CoA binding protein (ACBP) encoded by diazepam binding inhibitor (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABAAR) γ2 subunit (GABAARγ2). Here, we show that lipoanabolic diets cause an upregulation of GABAARγ2 protein in liver hepatocytes but not in other major organs. ACBP/DBI inhibition by systemically injected antibodies has been demonstrated to mediate anorexigenic and organ-protective, autophagy-dependent effects. Here, we set out to develop a new strategy for developing ACBP/DBI antagonists. For this, we built a molecular model of the interaction of ACBP/DBI with peptides derived from GABAARγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABAARγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABAARγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABAARγ2-derived eicosapeptide (but not its F77I-mutated control) blocked appetite stimulation by recombinant ACBP/DBI in vivo, induced autophagy in the liver, and protected mice against the hepatotoxin concanavalin A. We conclude that peptidomimetics disrupting the interaction between ACBP/DBI and GABAARγ2 might be used as ACBP/DBI antagonists. This strategy might lead to the future development of clinically relevant small molecules of the ACBP/DBI system.

Publisher

Springer Science and Business Media LLC

Cited by 1 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

1. Obesity-Associated Colorectal Cancer;International Journal of Molecular Sciences;2024-08-14

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