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

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

Edité par CCSD ; National Academy of Sciences -

International audience. 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 Gabrg2 F77I mutation that abolishes ACBP/DBI binding to the GABA A 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.

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