Autophagy-dependent hepatocyte secretion of DBI/ACBP induced by glucocorticoids determines the pathogenesis of Cushing syndrome
Year: 2024
Type: article
Abstract: DBI/ACBP is a phylogenetically ancient hormone that stimulates appetite and lipo-anabolism. In response to starvation, DBI/ACBP is secreted through a noncanonical, macroautophagy/autophagy-dependent pathway. The physiological hunger reflex involves starvation-induced secretion of DBI/ACBP from multiple cell types. DBI/ACBP concentrations subsequently increase in extracellular fluids to stimulate food intake. Recently, we observed that glucocorticoids, which are endogenous stress hormones as well as anti-inflammatory drugs, upregulate DBI/ACBP expression at the transcriptional level and stimulate autophagy in hepatocytes, thereby causing a surge in circulating DBI/ACBP levels. Prolonged increase in glucocorticoid concentrations causes an extreme form of metabolic syndrome, dubbed “Cushing syndrome”, which is characterized by clinical features including hyperphagia, hyperdipsia, dyslipidemia, hyperinsulinemia, insulin resistance, lipodystrophy, visceral adiposity, steatosis, sarcopenia and osteoporosis. Mice and patients with Cushing syndrome exhibit supraphysiological DBI/ACBP plasma levels. Of note, neutralization of extracellular DBI/ACBP protein with antibodies or mutation of the DBI/ACBP receptor (i.e. the GABRG2 subunit of GABR [gamma-aminobutyric acid type A receptor]) renders mice resistant to the induction of Cushing syndrome. Similarly, knockout of Dbi/Acbp in hepatocytes suppresses the corticotherapy-induced surge in plasma DBI/ACBP concentrations and prevents the manifestation of most of the characteristics of Cushing syndrome. We conclude that autophagy-mediated secretion of DBI/ACBP by hepatocytes constitutes a critical step of the pathomechanism of Cushing syndrome. It is tempting to speculate that stress-induced chronic elevations of endogenous glucocorticoids also compromise human health due to the protracted augmentation of circulating DBI/ACBP concentrations.
Source: Autophagy
Authors: Hui Pan, Ai-Ling Tian, Fréderic Castinetti, Isabelle Martins, Oliver Kepp, Guido Kroemer
Institutions: Institut Gustave Roussy, Centre de Recherche des Cordeliers, La Ligue Contre le Cancer, Analyse moléculaire, modélisation et imagerie de la maladie cancéreuse, Fondation Gustave Roussy, Assistance Publique Hôpitaux de Marseille, Hôpital de la Conception, Assistance Publique – Hôpitaux de Paris, Hôpital Européen Georges-Pompidou
Language: English
Subfield: Endocrine and Autonomic Systems
Field: Neuroscience
Domain: Life Sciences
Open Access status: bronze
Funders: Association pour la Recherche sur le Cancer, Seerave Foundation, Equipex, European Commission, Agence Nationale de la Recherche, Fondation pour la Recherche Médicale, Ligue Contre le Cancer, China Scholarship Council, Centre National de la Recherche Scientifique, Institut Universitaire de France, Institut National Du Cancer, European Research Council, Labex Immuno-Oncology
Awards: G1056382719, G111579892, Next-generation phenotypic screening for oncological applications, Coherent Raman Imaging for the Molecular Study of the OrigiN of diseases, G2045273392, Biomarkers affecting the transition from cardiovascular disease to lung cancer: towards stratified interception., G2786066923, G2980289319, G3231222199, G330243840, G3423759144, G3853421405, G434337789, G4656594441, G5674527738, Metabolic and Autophagic Control by Acyl CoA Binding Protein (ACBP/DBI), G6759347373, G7041469554, G7101784390, G82931992, G8401059989, Université de Paris
OpenAlex ID: W4405345333