ACBP/DBI neutralization for the prevention and treatment of malignant and non-malignant liver diseases
Sijing Li1, Flavia Lambertucci1, Léa Montégut1
1Team « Metabolism, Cancer & Immunity », Équipe labellisée par la Ligue contre le cancer, Centre de Recherche des Cordeliers U1138, Inserm, Université Paris Cité, Sorbonne Université, Paris, France.
Abstract:
Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI), suppresses autophagy, stimulates food intake, and regulates body composition. This tissue hormone contributes to the development of age-related diseases such as metabolic syndrome, cardiovascular disease, cancer, and osteoarthritis. ACBP/DBI also plays a key pathogenic role in liver disorders, including hepatocellular carcinoma (HCC). Circulating levels of ACBP/DBI are elevated in patients with histologically diagnosed steatosis, liver fibrosis or HCC, and correlate with disease severity. Moreover, the incidence of liver cancers increases in individuals receiving benzodiazepines, which act on the same binding sites of the GABA-A receptor as ACBP/DBI. In mice, inhibiting ACBP/DBI, via inducible knockout, mutation of its receptor (the γ2 subunit of the GABA-A receptor) or antibody-mediated neutralization, alleviates various liver conditions, including ischemia-reperfusion injury, bile duct obstruction, hepatotoxicity of acetaminophen, CCl4, ethanol, or concanavalin A, metabolic dysfunction-associated fatty liver disease, and HCC. Importantly, the anti-tumor effects of ACBP/DBI neutralization are not solely due to its hepatoprotective properties, as they persist in mouse models of HCC driven by oncogenes (e.g., β-catenin and MYC) or orthotopic injection of syngeneic liver cancer cells into immunocompetent hosts. Notably, hepatocellular carcinoma (HCC) is one of the few cancers in which elevated local ACBP/DBI expression is associated with poor clinical prognosis. In sum, ACBP/DBI functions as both a biomarker and a potential therapeutic target for malignant and non-malignant liver diseases.
Insights
Acyl coenzyme A binding protein (ACBP), or diazepam binding inhibitor (DBI), promotes liver disease and cancer. Inhibiting ACBP/DBI shows promise in treating various liver conditions and hepatocellular carcinoma in mice.
Area of Science:
- Biochemistry
- Hepatology
- Oncology
Background:
- Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI), is a hormone implicated in metabolic regulation and age-related diseases.
- ACBP/DBI plays a significant role in liver disorders, including hepatocellular carcinoma (HCC), with elevated circulating levels correlating with disease severity.
- Benzodiazepine use is linked to increased liver cancer incidence, suggesting a role for ACBP/DBI in hepatocarcinogenesis.
Purpose of the Study:
- To investigate the role of ACBP/DBI in liver diseases and its potential as a therapeutic target.
- To evaluate the efficacy of ACBP/DBI inhibition in preclinical models of liver conditions and HCC.
Main Methods:
- Studies involved ACBP/DBI inhibition in mice using inducible knockout, receptor mutation, and antibody-mediated neutralization.
- Preclinical models included various liver injuries (ischemia-reperfusion, toxicities, metabolic dysfunction) and HCC models (oncogene-driven and orthotopic injection).
Main Results:
- ACBP/DBI inhibition alleviated a wide range of liver conditions in mice, including metabolic dysfunction-associated fatty liver disease and HCC.
- Neutralization of ACBP/DBI demonstrated anti-tumor effects in HCC models, independent of general hepatoprotective properties.
- Elevated ACBP/DBI expression in HCC patients is associated with a poor clinical prognosis.
Conclusions:
- ACBP/DBI is a critical factor in the pathogenesis of both non-malignant and malignant liver diseases.
- Targeting ACBP/DBI represents a promising therapeutic strategy for liver disorders and hepatocellular carcinoma.
- ACBP/DBI serves as a valuable biomarker for liver disease severity and patient prognosis.
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