ACBP/DBI protein neutralization confers autophagy-dependent organ protection through inhibition of cell loss, inflammation, and fibrosis

Omar Motiño, Flavia Lambertucci, Gerasimos Anagnostopoulos, Sijing Li, Jihoon Nah, Francesca Castoldi, Laura Senovilla, Léa Montégut, Hui Chen, Sylvère Durand, Mélanie Bourgin, Fanny Aprahamian, Nitharsshini Nirmalathasan, Karla Alvarez-Valadez, Allan Sauvat, Vincent Carbonnier, Mojgan Djavaheri-Mergny, Federico Pietrocola, Junichi Sadoshima, Maria Chiara MaiuriIsabelle Martins, Guido Kroemer

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

Acyl-coenzyme A (CoA)–binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular feedback regulator of autophagy. Here, we report that injection of a monoclonal antibody neutralizing ACBP/DBI (α-DBI) protects the murine liver against ischemia/reperfusion damage, intoxication by acetaminophen and concanavalin A, and nonalcoholic steatohepatitis caused by methionine/choline-deficient diet as well as against liver fibrosis induced by bile duct ligation or carbon tetrachloride. α-DBI downregulated proinflammatory and profibrotic genes and upregulated antioxidant defenses and fatty acid oxidation in the liver. The hepatoprotective effects of α-DBI were mimicked by the induction of ACBP/DBI-specific autoantibodies, an inducible Acbp/Dbi knockout or a constitutive Gabrg2F77I mutation that abolishes ACBP/DBI binding to the GABAA receptor. Liver-protective α-DBI effects were lost when autophagy was pharmacologically blocked or genetically inhibited by knockout of Atg4b. Of note, α-DBI also reduced myocardium infarction and lung fibrosis, supporting the contention that it mediates broad organ-protective effects against multiple insults.

Original languageEnglish (US)
Article numbere2207344119
JournalProceedings of the National Academy of Sciences of the United States of America
Volume119
Issue number41
DOIs
StatePublished - Oct 11 2022
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General

Keywords

  • acyl-CoA binding protein
  • autophagy
  • fibrosis
  • myocardium infarction
  • non-alcoholic steatohepatitis

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