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Inhibition of acyl-CoA binding protein (ACBP) by means of a GABA_ARγ2-derived peptide.

ABSTRACT: Acyl-CoA binding protein (ACBP) encoded by diazepam binding inhibitor (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABA_AR) γ2 subunit (GABA_ARγ2). Here, we show that lipoanabolic diets cause an upregulation of GABA_ARγ2 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 GABA_ARγ2. We then validated the interaction between recombinant and native ACBP/DBI protein and a GABA_ARγ2-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABA_ARγ2-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP/DBI protein in vitro. Moreover, the GABA_ARγ2-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 GABA_ARγ2 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.

SUBMITTER: Anagnostopoulos G

PROVIDER: S-EPMC10998878 | biostudies-literature | 2024 Apr

REPOSITORIES: biostudies-literature

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

Anagnostopoulos Gerasimos G Saavedra Ester E Lambertucci Flavia F Motiño Omar O Dimitrov Jordan J Roiz-Valle David D Quesada Victor V Alvarez-Valadez Karla K Chen Hui H Sauvat Allan A Rong Yan Y Nogueira-Recalde Uxía U Li Sijing S Montégut Léa L Djavaheri-Mergny Mojgan M Castedo Maria M Lopez-Otin Carlos C Maiuri Maria Chiara MC Martins Isabelle I Kroemer Guido G

Cell death & disease 20240406 4

Acyl-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-d ...[more]

PMID: 38582872

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Project description:Acyl CoA binding protein encoded by diazepam binding inhibitor (ACBP/DBI) is a tissue hormone that stimulates lipo-anabolic responses and inhibits autophagy, thus contributing to aging and age-related diseases. Protein expression profiling of ACBP/DBI was performed on mouse tissues to identify organs in which this major tissue hormone is expressed. Transcriptomic and proteomic data bases corroborated a high level of human-mouse interspecies conservation of ACBP/DBI expression in different organs. Single-cell RNA-seq data confirmed that ACBP/DBI was strongly expressed by parenchymatous cells from specific human and mouse organs (e.g., kidney, large intestine, liver, lung) as well as by myeloid or glial cells from other organs (e.g., adipose tissue, brain, eye) following a pattern that was conserved among the two species. We identified a panel of 44 mRNAs that are strongly co-expressed with ACBP/DBI mRNA in normal and malignant human and normal mouse tissues. Of note, 22 (50%) of these co-expressed mRNAs encode proteins localized at mitochondria, and mRNAs with metabolism-related functions are strongly overrepresented (66%). Systematic data mining was performed to identify transcription factors that regulate ACBP/DBI expression in human and mouse. Several transcription factors, including growth response 1 (EGR1), E2F Transcription Factor 1 (E2F1, which interacts with retinoblastoma, RB) and transformation-related protein 53 (TRP53, best known as p53), which are endowed with oncosuppressive effects, consistently repress ACBP/DBI expression as well as its co-expressed mRNAs across multiple datasets, suggesting a mechanistic basis for a coregulation network. Furthermore, we identified multiple transcription factors that transactivate ACBP/DBI gene expression together with its coregulation network. Altogether, this study indicates the existence of conserved mechanisms determining the expression of ACBP/DBI in specific cell types of the mammalian organism.

Dataset Information

Inhibition of acyl-CoA binding protein (ACBP) by means of a GABA_ARγ2-derived peptide.

Publications

Inhibition of acyl-CoA binding protein (ACBP) by means of a GABA<sub>A</sub>Rγ2-derived peptide.

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