Pathogenic role of acyl coenzyme A binding protein (ACBP) in Cushing's syndrome

Hui Pan; Ai-Ling Tian; Hui Chen; Yifan Xia; Allan Sauvat; Stephanie Moriceau; Flavia Lambertucci; Omar Motiño; Liwei Zhao; Peng Liu; Misha Mao; Sijing Li; Shuai Zhang; Adrien Joseph; Sylvère Durand; Fanny Aprahamian; Zeyu Luo; Yang Ou; Zhe Shen; Enfu Xue; Yuhong Pan; Vincent Carbonnier; Gautier Stoll; Sabrina Forveille; Marion Leduc; Giulia Cerrato; Alexandra Cerone; Maria Chiara Maiuri; Frederic Castinetti; Thierry Brue; Hongsheng Wang; Yuting Ma; Isabelle Martins; Oliver Kepp; Guido Kroemer

doi:10.1038/s42255-024-01170-0

Pathogenic role of acyl coenzyme A binding protein (ACBP) in Cushing's syndrome

Nat Metab. 2024 Dec;6(12):2281-2299. doi: 10.1038/s42255-024-01170-0. Epub 2024 Nov 22.

Authors

Hui Pan^#^{1

2

3}, Ai-Ling Tian^#^{1

2

3}, Hui Chen^{1

2

3}, Yifan Xia⁴, Allan Sauvat^{1

2}, Stephanie Moriceau⁵, Flavia Lambertucci^{1

2}, Omar Motiño^{1

2}, Liwei Zhao^{1

2}, Peng Liu^{1

2}, Misha Mao^{1

2

3

6}, Sijing Li^{1

2

3}, Shuai Zhang^{1

2

3

7}, Adrien Joseph^{1

2

8}, Sylvère Durand^{1

2}, Fanny Aprahamian^{1

2}, Zeyu Luo⁹, Yang Ou¹⁰, Zhe Shen^{1

2

3}, Enfu Xue^{1

2

3}, Yuhong Pan^{1

2

3

11}, Vincent Carbonnier^{1

2}, Gautier Stoll^{1

2}, Sabrina Forveille^{1

2}, Marion Leduc^{1

2}, Giulia Cerrato^{1

2}, Alexandra Cerone^{1

2}, Maria Chiara Maiuri^{1

2}, Frederic Castinetti¹², Thierry Brue¹², Hongsheng Wang^{13

14}, Yuting Ma⁴, Isabelle Martins^{15

16}, Oliver Kepp^{17

18}, Guido Kroemer^{19

20

21}

Affiliations

¹ Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Institut, Villejuif, France.
² Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, INSERM U1138, Université Paris Cité, Sorbonne Université, Paris, France.
³ Faculté de Médecine, Université Paris-Saclay, Paris, France.
⁴ National Key Laboratory of Immunity and Inflammation, Suzhou Institute of Systems Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Suzhou, China.
⁵ Institut Imagine, Platform for Neurobehavioral and Metabolism, Structure Federative de Recherche Necker, 26 INSERM US24/CNRS UAR, Paris, France.
⁶ Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou, China.
⁷ Department of Respiratory and Critical Care Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁸ Service de Réanimation Medicale, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, Paris, France.
⁹ Department of Orthopedics, West China Hospital/West China School of Medicine, Sichuan University, Chengdu, China.
¹⁰ Center for Tumor Diagnosis and Therapy, Jinshan Hospital, Fudan University, Shanghai, China.
¹¹ Research Center of Avian Disease, College of Veterinary Medicine, Sichuan Agricultural University, Chengdu, China.
¹² Assistance Publique Hôpitaux de Marseille, Department of Endocrinology, La Conception Hospital, Marseille, France.
¹³ Department of Mycobacterium, Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Institute of Dermatology and Hospital for Skin Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
¹⁴ Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
¹⁵ Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Institut, Villejuif, France. [email protected].
¹⁶ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, INSERM U1138, Université Paris Cité, Sorbonne Université, Paris, France. [email protected].
¹⁷ Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Institut, Villejuif, France. [email protected].
¹⁸ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, INSERM U1138, Université Paris Cité, Sorbonne Université, Paris, France. [email protected].
¹⁹ Metabolomics and Cell Biology Platforms, UMS AMMICa, Gustave Roussy Institut, Villejuif, France. [email protected].
²⁰ Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, INSERM U1138, Université Paris Cité, Sorbonne Université, Paris, France. [email protected].
²¹ Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, Paris, France. [email protected].

^# Contributed equally.

Abstract

Cushing's syndrome is caused by an elevation of endogenous or pharmacologically administered glucocorticoids. Acyl coenzyme A binding protein (ACBP, encoded by the gene diazepam binding inhibitor, Dbi) stimulates food intake and lipo-anabolic reactions. Here we found that plasma ACBP/DBI concentrations were elevated in patients and mice with Cushing's syndrome. We used several methods for ACBP/DBI inhibition in mice, namely, (1) induction of ACBP/DBI autoantibodies, (2) injection of a neutralizing monoclonal antibody, (3) body-wide or hepatocyte-specific knockout of the Dbi gene, (4) mutation of the ACBP/DBI receptor Gabrg2 and (5) injections of triiodothyronine or (6) the thyroid hormone receptor-β agonist resmetirom to block Dbi transcription. These six approaches abolished manifestations of Cushing's syndrome such as increased food intake, weight gain, excessive adiposity, liver damage, hypertriglyceridaemia and type 2 diabetes. In conclusion, it appears that ACBP/DBI constitutes an actionable target that is causally involved in the development of Cushing's syndrome.

MeSH terms

Animals
Cushing Syndrome* / metabolism
Diazepam Binding Inhibitor* / metabolism
Female
Humans
Male
Mice
Mice, Knockout

Substances

Diazepam Binding Inhibitor