ACBP/DBI neutralization for the experimental treatment of fatty liver disease
Omar Motiño, Flavia Lambertucci, Adrien Joseph, Sylvère Durand, Gerasimos Anagnostopoulos, Sijing Li, Vincent Carbonnier, Uxía Nogueira-Recalde, Léa Montégut, Hui Chen, Fanny Aprahamian, Nitharsshini Nirmalathasan, Maria Chiara Maiuri, Federico Pietrocola, Dominique Valla, Cédric Laouenan, Jean–François Gautier, Laurent Castéra, QUID NASH Investigators, Laurent Castéra, Anaïs Vallet‐Pichard, Tiphaine Vidal-Trécan, Pauline Manchon, Valérie Paradis, Dominique Roulot, Christian Boîtard, Benoît Terris, H. Bihan, Jean‐Baptiste Julla, Thierry Poynard, Angélique Bzrustowski, Étienne Larger, S. Czernichow, Stanislas Pol, Pierre Bédossa, Christophe Junot, Nathalie de Préville, Isabelle Durand‐Zaleski, Pierre‐Emmanuel Rautou, Bernard E. Van Beers, Marco Dioguardi Burgio, Valérie Vilgrain, Jean-Marie Correas, Philippe Garteiser, Jean-Pierre Riveline, Mark Ibberson, Isabelle Martins, Guido Kroemer
Abstract
Abstract Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl 4 , and (iv) a combination of CCl 4 injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.