Low-density lipoprotein receptor-related protein 1 deficiency in cardiomyocytes reduces susceptibility to insulin resistance and obesity

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 signaling activation 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.

This work was funded by FIS PI14/01729 and FIS PI18/01584 (to VLl-C), FIS16/00139 (to JCE-G) grants from Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (E.F.R.D.) and by the Ministry of Spain-MINECO (SAF2014-52223-C2-1-R to DS, co-financed by the European Fund for Regional Development (E.F.R.D.). Support was received from Ministerio de Economía y Competitividad to DdG-C (IJCI-2016-29393), Agència de Gestió d'Ajuts Universitaris i de Recerca Grant FI to ERL (FI-DGR 2013/00014), Fundació MARATÓ TV3 Project 201521-10 (to VLl-C) and Project 87/C/2016 to DS. CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM; CB07/08/0016 (FBV, JCE-G, LC); CB07/08/0017 (AZ), CIBER Fisiopatología de la Obesidad y la Nutrición (CIBEROBN; CB06/03/0001 (DS, LH); CB06/03/0017 (JCL, NR)) and CIBER Enfermedades Cardiovasculares (CIBERCV; CB16/1100403) (DdG-C, VLl-, CS, ERL and AB-G) are Instituto de Salud Carlos III (ISCIII) projects.