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Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy
- Publication Year :
- 2014
- Publisher :
- American Society for Clinical Investigation, 2014.
-
Abstract
- Patients with type 2 diabetes often present with cardiovascular complications; however, it is not clear how diabetes promotes cardiac dysfunction. In murine models, deletion of the gene encoding aryl hydrocarbon nuclear translocator (ARNT, also known as HIF1β) in the liver or pancreas leads to a diabetic phenotype; however, the role of ARNT in cardiac metabolism is unknown. Here, we determined that cardiac-specific deletion of Arnt in adult mice results in rapid development of cardiomyopathy (CM) that is characterized by accumulation of lipid droplets. Compared with hearts from ARNT-expressing mice, ex vivo analysis of ARNT-deficient hearts revealed a 2-fold increase in fatty acid (FA) oxidation as well as a substantial increase in the expression of PPARα and its target genes. Furthermore, deletion of both Arnt and Ppara preserved cardiac function, improved survival, and completely reversed the FA accumulation phenotype, indicating that PPARα mediates the detrimental effects of Arnt deletion in the heart. Finally, we determined that ARNT directly regulates Ppara expression by binding to its promoter and forming a complex with HIF2α. Together, these findings suggest that ARNT is a critical regulator of myocardial FA metabolism and that its deletion leads to CM and an increase in triglyceride accumulation through PPARα.
- Subjects :
- medicine.medical_specialty
Aryl hydrocarbon receptor nuclear translocator
Transcription, Genetic
Diabetic Cardiomyopathies
Cardiomyopathy
Peroxisome proliferator-activated receptor
Mice, Obese
Biology
Rats, Sprague-Dawley
Gene Knockout Techniques
Lipid droplet
Internal medicine
Diabetic cardiomyopathy
medicine
Animals
Humans
PPAR alpha
Triglycerides
Regulation of gene expression
chemistry.chemical_classification
Mice, Knockout
Ventricular Remodeling
Myocardium
Aryl Hydrocarbon Receptor Nuclear Translocator
Fatty Acids
Lipid metabolism
General Medicine
medicine.disease
Lipid Metabolism
Endocrinology
HEK293 Cells
chemistry
Lipotoxicity
Gene Expression Regulation
Oxidation-Reduction
Research Article
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....ff200ca90dece3b3cae9534f6374f919