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| Pàgina inicial > Articles > Articles publicats > Low-density lipoprotein receptor-related protein 1 deficiency in cardiomyocytes reduces susceptibility to insulin resistance and obesity |
(Institut d'Investigació Biomèdica Sant Pau) (Institut Germans Trias i Pujol) (Institut d'Investigació Biomèdica Sant Pau) (Universitat de Barcelona. Departament de Bioquímica i Fisiologia) (Institut Germans Trias i Pujol) (Institut d'Investigaciones Biomèdiques de Barcelona) (Institut d'Investigaciones Biomèdiques de Barcelona) (Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina) (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular) (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol) (Universitat de Barcelona. Departament de Bioquímica i Fisiologia) (Institut d'Investigació Biomèdica Sant Pau) (Institut Germans Trias i Pujol)
| Data: | 2020 |
| Resum: | Background: Low-density lipoprotein receptor-related protein 1 (LRP1) plays a key role in fatty acid metabolism and glucose homeostasis. In the context of dyslipemia, LRP1 is upregulated in the heart. Our aim was to evaluate the impact of cardiomyocyte LRP1 deficiency on high fat diet (HFD)-induced cardiac and metabolic alterations, and to explore the potential mechanisms involved. Methods: We used TnT-iCre transgenic mice with thoroughly tested suitability to delete genes exclusively in cardiomyocytes to generate an experimental mouse model with conditional Lrp1 deficiency in cardiomyocytes (TNT-iCre+-LRP1flox/flox). Findings: Mice with Lrp1-deficient cardiomyocytes (cm-Lrp1−/−) have a normal cardiac function combined with a favorable metabolic phenotype against HFD-induced glucose intolerance and obesity. Glucose intolerance protection was linked to higher hepatic fatty acid oxidation (FAO), lower liver steatosis and increased whole-body energy expenditure. Proteomic studies of the heart revealed decreased levels of cardiac pro-atrial natriuretic peptide (pro-ANP), which was parallel to higher ANP circulating levels. cm-Lrp1−/− mice showed ANP signalingactivation that was linked to increased fatty acid (FA) uptake and increased AMPK/ ACC phosphorylation in the liver. Natriuretic peptide receptor A (NPR-A) antagonist completely abolished ANP signaling and metabolic protection in cm-Lrp1−/− mice. Conclusions: These results indicate that an ANP-dependent axis controlled by cardiac LRP1 levels modulates AMPK activity in the liver, energy homeostasis and whole-body metabolism. |
| Ajuts: | Ministerio de Economía y Competitividad PI14/01729 Instituto de Salud Carlos III PI18/01584 Ministerio de Economía y Competitividad PI16/00139 Ministerio de Economía y Competitividad SAF2014-52223-C2-1-R Ministerio de Economía y Competitividad IJCI-2016-29393 Agència de Gestió d'Ajuts Universitaris i de Recerca FI-DGR 2013/00014 |
| Nota: | Altres ajuts: Fundació La Marató TV3, projectes 201521-10 87/C/2016 |
| Drets: | Tots els drets reservats.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió de l'autor |
| Matèria: | SDG 3 - Good Health and Well-being ; Cardiomyocyte ; Lrp1 ; ANP ; Heart ; Liver ; AMPK ; Fatty acid oxidation |
| Publicat a: | Metabolism: Clinical and Experimental, Vol. 160 (may 2020) , ISSN 1532-8600 |
