Publicaciones científicas

Liver CPT1A gene therapy reduces diet-induced hepatic steatosis in mice and highlights potential lipid biomarkers for human NAFLD

15-jul-2020 | Revista: FASEB Journal

Minéia Weber  (1), Paula Mera  (1, 2), Josefina Casas  (3, 4), Javier Salvador  (2, 5), Amaia Rodríguez  (2, 6), Sergio Alonso  (7), David Sebastián  (8, 9), M Carmen Soler-Vázquez  (1), Carla Montironi  (10, 11), Sandra Recalde  (1), Raquel Fucho  (1), María Calderón-Domínguez  (1), Joan Francesc Mir  (1), Ramon Bartrons  (12), Joan Carles Escola-Gil  (9, 13) , David Sánchez-Infantes  (2, 14) , Antonio Zorzano  (8, 9) , Vicenta Llorente-Cortes  (15, 16   17), Núria Casals  (2, 18), Víctor Valentí  (6, 19), Gema Frühbeck  (2, 6), Laura Herrero  (1, 2), Dolors Serra  (1, 2)

(1) Department of Biochemistry and Physiology, School of Pharmacy and Food Sciences, Institut de Biomedicina de la Universitat de Barcelona (IBUB), Universitat de Barcelona, Barcelona, Spain.
(2) Centro de Investigación Biomédica en Red de Fisiopatología de la Obesidad y la Nutrición (CIBEROBN), Instituto de Salud Carlos III, Madrid, Spain.
(3) Research Unit on BioActive Molecules, Department of Biological Chemistry, Institute of Advanced Chemistry of Catalonia (IQAC)/CSIC, Barcelona, Spain.
(4) Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain.
(5) Department of Endocrinology & Nutrition, Clínica Universidad de Navarra, Pamplona, Spain.
(6) Metabolic Research Laboratory, Clínica Universidad de Navarra, IdiSNA, Pamplona, Spain.
(7) Cancer Genetics and Epigenetics Group, Program of Predictive and Personalized Medicine of Cancer, Germans Trias i Pujol Research Institute (IGTP-PMPPC), Campus Can Ruti, Barcelona, Spain.
(8) Institute for Research in Biomedicine (IRB Barcelona), Barcelona Institute of Science and Technology, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain.
(9) Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Instituto de Salud Carlos III, Madrid, Spain.
(10) Pathology Department, Hospital Clinic de Barcelona, Barcelona, Spain.
(11) Liver Cancer Translational Research Laboratory, Liver Unit, IDIBAPS-Hospital Clínic, Universitat de Barcelona, Barcelona, Spain.
(12) Departament de Ciències Fisiològiques, Facultat de Medicina i Ciències de la Salut, Universitat de Barcelona, Spain.
(13) IIB Sant Pau, Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Barcelona, Spain.
(14) Germans Trias i Pujol Research Institute (IGTP-PMPPC), Campus Can Ruti, Barcelona, Spain.
(15) Institute of Biomedical Research of Barcelona (IIBB), Spanish National Research Council (CSIC), Biomedical Research Institute Sant Pau (IIB Sant Pau), Barcelona, Spain.
(16) CIBERCV, Institute of Health Carlos III, Madrid, Spain.
(17) Cardiovascular Research Center, CSIC-ICCC, Barcelona, Spain.
(18) Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Sant Cugat del Vallès, Spain.
(19) Department of Surgery, Clínica Universidad de Navarra, Pamplona, Spain.


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.

CITA DEL ARTÍCULO  FASEB J . 2020 Jul 15.  doi: 10.1096/fj.202000678R

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