Liver CPT1A gene therapy reduces diet‐induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD
Author
Weber, Minéia
Mera, Paula
Casas, Josefina
Salvador, Javier
Rodríguez, Amaia
Alonso, Sergio
Sebastián, David
Soler-Vázquez, M. Carmen
Montironi, Carla
Recalde, Sandra
Fucho, Raquel
Calderón-Domínguez, María
Mir, Joan Francesc
Bartrons, Ramon
Escola-Gil, Joan Carles
Sánchez-Infantes, David
Zorzano, Antonio
Llorente-Cortes, Vicenta
Casals i Farré, Núria
Valentí, Víctor
Frühbeck, Gema
Herrero Rodríguez, Laura
Serra, Dolors
Publication date
2020ISSN
0892-6638
Abstract
The prevalence of nonalcoholic fatty liver disease (NAFLD) has increased drastically due to the global obesity pandemic but at present there are no approved therapies. Here, we aimed to revert high‐fat diet (HFD)‐induced obesity and NAFLD in mice by enhancing liver fatty acid oxidation (FAO). Moreover, we searched for potential new lipid biomarkers for monitoring liver steatosis in humans. We used adeno‐associated virus (AAV) to deliver a permanently active mutant form of human carnitine palmitoyltransferase 1A (hCPT1AM), the key enzyme in FAO, in the liver of a mouse model of HFD‐induced obesity and NAFLD. Expression of hCPT1AM enhanced hepatic FAO and autophagy, reduced liver steatosis, and improved glucose homeostasis. Lipidomic analysis in mice and humans before and after therapeutic interventions, such as hepatic AAV9‐hCPT1AM administration and RYGB surgery, respectively, led to the identification of specific triacylglyceride (TAG) specie (C50:1) as a potential biomarker to monitor NAFFLD disease. To sum up, here we show for the first time that liver hCPT1AM gene therapy in a mouse model of established obesity, diabetes, and NAFLD can reduce HFD‐induced derangements. Moreover, our study highlights TAG (C50:1) as a potential noninvasive biomarker that might be useful to monitor NAFLD in mice and humans.
Document Type
Article
Document version
Published version
Language
English
Subject (CDU)
61 - Medical sciences
616.4 - Pathology of the lymphatic system, haemopoietic (haematopoietic) organs, endocrines
Keywords
Oxidació
Àcids grassos
Teràpia genètica
Esteatosi hepàtica
Marcadors bioquímics
Obesitat
Fetge
Oxidación
Ácidos grasos
Terapia genética
Esteatosis hepática
Marcadores bioquímicos
Obesidad
Hígado
Oxidation
Fatty acids
Genetic therapy
Hepatic steatosis
Biochemical markers
Obesity
Liver
Pages
22
Publisher
John Wiley & Sons, Inc.
Collection
34; 9
Is part of
Federation of American Societies for Experimental Biology
Citation
Weber, Minéia; Mera, Paula; Casas, Josefina [et al.]. Liver CPT1A gene therapy reduces diet‐induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD. Federation of American Societies for Experimental Biology, 2020, 34(9), p. 11816–11837. Disponible en: <https://faseb.onlinelibrary.wiley.com/doi/full/10.1096/fj.202000678R>. Fecha de acceso: 29 oct. 2020. DOI: 10.1096/fj.202000678R
Grant agreement number
info:eu-repo/grantAgreement/ES/1PE/SAF2014-52223-C2-1-R
info:eu-repo/grantAgreement/ES/2PE/SAF2017-83813-C3-1-R
info:eu-repo/grantAgreement/ES/2PE/SAF2017-82813-C3-3R
This item appears in the following Collection(s)
- Ciències de la Salut [745]
Rights
© 2020 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by-nc/4.0/