{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T21:38:43Z","timestamp":1787002723523,"version":"build-2736575974"},"reference-count":28,"publisher":"Springer Science and Business Media LLC","issue":"4","license":[{"start":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T00:00:00Z","timestamp":1712361600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T00:00:00Z","timestamp":1712361600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Acyl-CoA binding protein (ACBP) encoded by\n                    <jats:italic>diazepam binding inhibitor<\/jats:italic>\n                    (DBI) is an extracellular inhibitor of autophagy acting on the gamma-aminobutyric acid A receptor (GABA\n                    <jats:sub>A<\/jats:sub>\n                    R) \u03b32 subunit (GABA\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32). Here, we show that lipoanabolic diets cause an upregulation of GABA\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32 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\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32. We then validated the interaction between recombinant and native ACBP\/DBI protein and a GABA\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32-derived eicosapeptide (but not its F77I mutant) by pull down experiments or surface plasmon resonance. The GABA\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32-derived eicosapeptide inhibited the metabolic activation of hepatocytes by recombinant ACBP\/DBI protein in vitro. Moreover, the GABA\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32-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\n                    <jats:sub>A<\/jats:sub>\n                    R\u03b32 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.\n                  <\/jats:p>","DOI":"10.1038\/s41419-024-06633-6","type":"journal-article","created":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T03:01:36Z","timestamp":1712372496000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Inhibition of acyl-CoA binding protein (ACBP) by means of a GABAAR\u03b32-derived peptide"],"prefix":"10.1038","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2042-8675","authenticated-orcid":false,"given":"Gerasimos","family":"Anagnostopoulos","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ester","family":"Saavedra","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flavia","family":"Lambertucci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-0966","authenticated-orcid":false,"given":"Omar","family":"Moti\u00f1o","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8536-8995","authenticated-orcid":false,"given":"Jordan","family":"Dimitrov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Roiz-Valle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Quesada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karla","family":"Alvarez-Valadez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7076-8638","authenticated-orcid":false,"given":"Allan","family":"Sauvat","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Rong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ux\u00eda","family":"Nogueira-Recalde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sijing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"L\u00e9a","family":"Mont\u00e9gut","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mojgan","family":"Djavaheri-Mergny","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Castedo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos","family":"Lopez-Otin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9760-7674","authenticated-orcid":false,"given":"Maria Chiara","family":"Maiuri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0885-613X","authenticated-orcid":false,"given":"Isabelle","family":"Martins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9334-4405","authenticated-orcid":false,"given":"Guido","family":"Kroemer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2024,4,6]]},"reference":[{"key":"6633_CR1","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.plipres.2015.04.001","volume":"59","author":"D Neess","year":"2015","unstructured":"Neess D, Bek S, Engelsby H, Gallego SF, Faergeman NJ. Long-chain acyl-CoA esters in metabolism and signaling: role of acyl-CoA binding proteins. Prog Lipid Res. 2015;59:1\u201325.","journal-title":"Prog Lipid Res"},{"key":"6633_CR2","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.plipres.2016.06.002","volume":"63","author":"ZY Du","year":"2016","unstructured":"Du ZY, Arias T, Meng W, Chye ML. Plant acyl-CoA-binding proteins: an emerging family involved in plant development and stress responses. Prog Lipid Res. 2016;63:165\u201381.","journal-title":"Prog Lipid Res"},{"key":"6633_CR3","doi-asserted-by":"publisher","first-page":"34","DOI":"10.3390\/jof6010034","volume":"6","author":"S Qiu","year":"2020","unstructured":"Qiu S, Zeng B. Advances in understanding the Acyl-CoA-binding protein in plants, mammals, yeast, and filamentous fungi. J Fungi. 2020;6:34.","journal-title":"J Fungi"},{"key":"6633_CR4","doi-asserted-by":"publisher","first-page":"e1001024","DOI":"10.1371\/journal.pgen.1001024","volume":"6","author":"P Fabrizio","year":"2010","unstructured":"Fabrizio P, Hoon S, Shamalnasab M, Galbani A, Wei M, Giaever G, et al. Genome-wide screen in Saccharomyces cerevisiae identifies vacuolar protein sorting, autophagy, biosynthetic, and tRNA methylation genes involved in life span regulation. PLoS Genet. 2010;6:e1001024.","journal-title":"PLoS Genet"},{"key":"6633_CR5","doi-asserted-by":"publisher","first-page":"1463","DOI":"10.1105\/tpc.110.075333","volume":"22","author":"S Xiao","year":"2010","unstructured":"Xiao S, Gao W, Chen QF, Chan SW, Zheng SX, Ma J, et al. Overexpression of Arabidopsis acyl-CoA binding protein ACBP3 promotes starvation-induced and age-dependent leaf senescence. Plant Cell. 2010;22:1463\u201382.","journal-title":"Plant Cell"},{"key":"6633_CR6","doi-asserted-by":"publisher","first-page":"802","DOI":"10.4161\/auto.6.6.12576","volume":"6","author":"S Xiao","year":"2010","unstructured":"Xiao S, Chye ML. The Arabidopsis thaliana ACBP3 regulates leaf senescence by modulating phospholipid metabolism and ATG8 stability. Autophagy. 2010;6:802\u20134.","journal-title":"Autophagy"},{"key":"6633_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-2205-x","volume":"11","author":"N Charmpilas","year":"2020","unstructured":"Charmpilas N, Ruckenstuhl C, Sica V, Buttner S, Habernig L, Dichtinger S, et al. Acyl-CoA-binding protein (ACBP): a phylogenetically conserved appetite stimulator. Cell Death Dis. 2020;11:7.","journal-title":"Cell Death Dis"},{"key":"6633_CR8","doi-asserted-by":"publisher","first-page":"754","DOI":"10.1016\/j.cmet.2019.07.010","volume":"30","author":"JM Bravo-San Pedro","year":"2019","unstructured":"Bravo-San Pedro JM, Sica V, Martins I, Pol J, Loos F, Maiuri MC, et al. Acyl-CoA-binding protein is a lipogenic factor that triggers food intake and obesity. Cell Metab. 2019;30:754\u201367.e759.","journal-title":"Cell Metab"},{"key":"6633_CR9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2207344119","volume":"119","author":"O Motino","year":"2022","unstructured":"Motino O, Lambertucci F, Anagnostopoulos G, Li S, Nah J, Castoldi F, et al. ACBP\/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis. Proc Natl Acad Sci USA. 2022;119:e2207344119.","journal-title":"Proc Natl Acad Sci USA"},{"key":"6633_CR10","doi-asserted-by":"publisher","first-page":"E413","DOI":"10.1210\/jc.2009-2534","volume":"96","author":"N Franck","year":"2011","unstructured":"Franck N, Gummesson A, Jernas M, Glad C, Svensson PA, Guillot G, et al. Identification of adipocyte genes regulated by caloric intake. J Clin Endocrinol Metab. 2011;96:E413\u2013418.","journal-title":"J Clin Endocrinol Metab"},{"key":"6633_CR11","doi-asserted-by":"publisher","first-page":"e9923","DOI":"10.1371\/journal.pone.0009923","volume":"5","author":"F Folli","year":"2010","unstructured":"Folli F, Guzzi V, Perego L, Coletta DK, Finzi G, Placidi C, et al. Proteomics reveals novel oxidative and glycolytic mechanisms in type 1 diabetic patients\u2019 skin which are normalized by kidney-pancreas transplantation. PLoS ONE. 2010;5:e9923.","journal-title":"PLoS ONE"},{"key":"6633_CR12","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1002\/hep.27695","volume":"61","author":"BM Arendt","year":"2015","unstructured":"Arendt BM, Comelli EM, Ma DW, Lou W, Teterina A, Kim T, et al. Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n-3 and n-6 polyunsaturated fatty acids. Hepatology. 2015;61:1565\u201378.","journal-title":"Hepatology"},{"key":"6633_CR13","doi-asserted-by":"publisher","first-page":"125","DOI":"10.1016\/j.neuron.2017.03.003","volume":"94","author":"I Dumitru","year":"2017","unstructured":"Dumitru I, Neitz A, Alfonso J, Monyer H. Diazepam binding inhibitor promotes stem cell expansion controlling environment-dependent neurogenesis. Neuron. 2017;94:125\u201337.e125.","journal-title":"Neuron"},{"key":"6633_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-022-04834-5","volume":"13","author":"G Anagnostopoulos","year":"2022","unstructured":"Anagnostopoulos G, Motino O, Li S, Carbonnier V, Chen H, Sica V, et al. An obesogenic feedforward loop involving PPARgamma, acyl-CoA binding protein and GABA(A) receptor. Cell Death Dis. 2022;13:356.","journal-title":"Cell Death Dis"},{"key":"6633_CR15","doi-asserted-by":"publisher","DOI":"10.1016\/j.xpro.2021.101095","volume":"3","author":"L Montegut","year":"2022","unstructured":"Montegut L, Chen H, Bravo-San Pedro JM, Motino O, Martins I, Kroemer G. Immunization of mice with the self-peptide ACBP coupled to keyhole limpet hemocyanin. STAR Protoc. 2022;3:101095.","journal-title":"STAR Protoc"},{"key":"6633_CR16","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-020-2716-5","volume":"11","author":"A Joseph","year":"2020","unstructured":"Joseph A, Moriceau S, Sica V, Anagnostopoulos G, Pol J, Martins I, et al. Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)\/diazepam binding inhibitor (DBI). Cell Death Dis. 2020;11:502.","journal-title":"Cell Death Dis"},{"key":"6633_CR17","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1091\/mbc.e03-09-0704","volume":"15","author":"N Mizushima","year":"2004","unstructured":"Mizushima N, Yamamoto A, Matsui M, Yoshimori T, Ohsumi Y. In vivo analysis of autophagy in response to nutrient starvation using transgenic mice expressing a fluorescent autophagosome marker. Mol Biol Cell. 2004;15:1101\u201311.","journal-title":"Mol Biol Cell"},{"key":"6633_CR18","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1007\/978-1-0716-3694-7_9","volume":"2769","author":"F Lambertucci","year":"2024","unstructured":"Lambertucci F, Motino O, Perez-Lanzon M, Li S, Plantureux C, Pol J, et al. Isolation of primary mouse hepatocytes and non-parenchymal cells from a liver with precancerous lesions. Methods Mol Biol. 2024;2769:109\u201328.","journal-title":"Methods Mol Biol"},{"key":"6633_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-27838-9","volume":"13","author":"T Tsaban","year":"2022","unstructured":"Tsaban T, Varga JK, Avraham O, Ben-Aharon Z, Khramushin A, Schueler-Furman O. Harnessing protein folding neural networks for peptide-protein docking. Nat Commun. 2022;13:176.","journal-title":"Nat Commun"},{"key":"6633_CR20","doi-asserted-by":"publisher","DOI":"10.1002\/pro.4792","volume":"32","author":"EC Meng","year":"2023","unstructured":"Meng EC, Goddard TD, Pettersen EF, Couch GS, Pearson ZJ, Morris JH, et al. UCSF ChimeraX: tools for structure building and analysis. Protein Sci. 2023;32:e4792.","journal-title":"Protein Sci"},{"key":"6633_CR21","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-03864-9","volume":"12","author":"A Joseph","year":"2021","unstructured":"Joseph A, Chen H, Anagnostopoulos G, Montegut L, Lafarge A, Motino O, et al. Effects of acyl-coenzyme A binding protein (ACBP)\/diazepam-binding inhibitor (DBI) on body mass index. Cell Death Dis. 2021;12:599.","journal-title":"Cell Death Dis"},{"key":"6633_CR22","doi-asserted-by":"publisher","first-page":"190","DOI":"10.1038\/s41586-022-04517-3","volume":"604","author":"A Sente","year":"2022","unstructured":"Sente A, Desai R, Naydenova K, Malinauskas T, Jounaidi Y, Miehling J, et al. Differential assembly diversifies GABA(A) receptor structures and signalling. Nature. 2022;604:190\u20134.","journal-title":"Nature"},{"key":"6633_CR23","doi-asserted-by":"publisher","DOI":"10.1186\/s12858-019-0108-1","volume":"20","author":"K Chamchoy","year":"2019","unstructured":"Chamchoy K, Pakotiprapha D, Pumirat P, Leartsakulpanich U, Boonyuen U. Application of WST-8 based colorimetric NAD(P)H detection for quantitative dehydrogenase assays. BMC Biochem. 2019;20:4.","journal-title":"BMC Biochem"},{"key":"6633_CR24","doi-asserted-by":"publisher","DOI":"10.1111\/acel.13751","volume":"22","author":"L Montegut","year":"2023","unstructured":"Montegut L, Joseph A, Chen H, Abdellatif M, Ruckenstuhl C, Motino O, et al. High plasma concentrations of acyl-coenzyme A binding protein (ACBP) predispose to cardiovascular disease: evidence for a phylogenetically conserved proaging function of ACBP. Aging Cell. 2023;22:e13751.","journal-title":"Aging Cell"},{"key":"6633_CR25","doi-asserted-by":"publisher","first-page":"e13910","DOI":"10.1111\/acel.13910","volume":"22","author":"L Montegut","year":"2023","unstructured":"Montegut L, Abdellatif M, Motino O, Madeo F, Martins I, Quesada V, et al. Acyl coenzyme A binding protein (ACBP): An aging- and disease-relevant \u201cautophagy checkpoint\u201d. Aging Cell. 2023;22:e13910.","journal-title":"Aging Cell"},{"key":"6633_CR26","doi-asserted-by":"publisher","first-page":"7148","DOI":"10.1523\/JNEUROSCI.2255-20.2021","volume":"41","author":"R Lamtahri","year":"2021","unstructured":"Lamtahri R, Hazime M, Gowing EK, Nagaraja RY, Maucotel J, Alasoadura M, et al. The Gliopeptide ODN, a ligand for the benzodiazepine site of GABA(A) receptors, boosts functional recovery after stroke. J Neurosci. 2021;41:7148\u201359.","journal-title":"J Neurosci"},{"key":"6633_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/s13054-014-0633-7","volume":"18","author":"T Clavier","year":"2014","unstructured":"Clavier T, Tonon MC, Foutel A, Besnier E, Lefevre-Scelles A, Morin F, et al. Increased plasma levels of endozepines, endogenous ligands of benzodiazepine receptors, during systemic inflammation: a prospective observational study. Crit Care. 2014;18:633.","journal-title":"Crit Care"},{"key":"6633_CR28","doi-asserted-by":"publisher","first-page":"1482","DOI":"10.1158\/2159-8290.CD-21-1156","volume":"12","author":"HK Koblish","year":"2022","unstructured":"Koblish HK, Wu L, Wang LS, Liu PCC, Wynn R, Rios-Doria J, et al. Characterization of INCB086550: a potent and novel small-molecule PD-L1 inhibitor. Cancer Discov. 2022;12:1482\u201399.","journal-title":"Cancer Discov"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06633-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06633-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06633-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,4,6]],"date-time":"2024-04-06T03:02:30Z","timestamp":1712372550000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-024-06633-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,4,6]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,4]]}},"alternative-id":["6633"],"URL":"https:\/\/doi.org\/10.1038\/s41419-024-06633-6","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,4,6]]},"assertion":[{"value":"10 December 2023","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2024","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"25 March 2024","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 April 2024","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"GK has been holding research contracts with Daiichi Sankyo, Eleor, Kaleido, Lytix Pharma, PharmaMar, Osasuna Therapeutics, Samsara Therapeutics, Sanofi, Tollys, and Vascage. GK has been consulting for Reithera. GK is on the Board of Directors of the Bristol Myers Squibb Foundation France. GK is a scientific co-founder of everImmune, Osasuna Therapeutics, Samsara Therapeutics and Therafast Bio. GK is in the scientific advisory boards of Hevolution, Institut Servier and Longevity Vision Funds. GK is the inventor of patents covering therapeutic targeting of aging, cancer, cystic fibrosis and metabolic disorders. GK, IM and OM are inventors of patent covering the therapeutic use of anti-ACBP\/DBI antibodies. GK\u2019s wife, Laurence Zitvogel, has held research contracts with Glaxo Smyth Kline, Incyte, Lytix, Kaleido, Innovate Pharma, Daiichi Sankyo, Pilege, Merus, Transgene, 9\u2009m, Tusk and Roche, was on the Board of Directors of Transgene, is a cofounder of everImmune, and holds patents covering the treatment of cancer and the therapeutic manipulation of the microbiota. GK\u2019s brother, Romano Kroemer, was an employee of Sanofi and now consults for Boehringer-Ingelheim. The others co-authors declare no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"All animal experiments were conducted in accordance with the local Animal Experimental Ethics Committee (protocols ##25355-2020050715057113 v4, ##31411-2021050411267667 v3, #31018-2021041210419925 v4 and #25000-2020040718432518 v4).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}}],"article-number":"249"}}