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

• DOI: 10.1073/pnas.2207344119
• Publication Date: 2022-10-03T19:17:41Z
• Authors: Omar Motiño; Flavia Lambertucci; Gerasimos Anagnos...; Sijing Li; Jihoon Nah; Francesca Castoldi; Laura Senovilla; Léa Montégut; Hui Chen; Sylvère Durand; Mélanie Bourgin; Fanny Aprahamian; Nitharsshini Nirm...; Karla Alvarez-Val...; Allan Sauvat; Vincent Carbonnier; Mojgan Djavaheri-...; Federico Pietrocola; Junichi Sadoshima; Maria Chiara Maiuri; Isabelle Martins; Guido Kroemer
• Keywords: autophagy; [SDV]Life Sciences [q-bio]; Acyl-CoA binding protein; Antioxidants; Choline; Mice; 03 medical and health sciences; Methionine; Myocardium infarction; Autophagy; Concanavalin A; Animals; myocardium infarction; Coenzyme A; acyl-CoA binding protein; Carbon Tetrachloride; Non-alcoholic steatohepatitis; Acetaminophen; Autoantibodies; Diazepam Binding Inhibitor; Inflammation; 0303 health sciences; Diazepam; fibrosis; Fatty Acids; Antibodies, Monoclonal; Biological Sciences; Receptors, GABA-A; Fibrosis; acyl-CoA binding protein; autophagy; fibrosis; myocardium infarction; non-alcoholic steatohepatitis; 3. Good health; non-alcoholic steatohepatitis; Carrier Proteins

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.