title: Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy.
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.
authors.forename: Rongxue
authors.initials: R
authors.lastname: Wu
authors.forename: Hsiang-Chun
authors.initials: HC
authors.lastname: Chang
authors.forename: Arineh
authors.initials: A
authors.lastname: Khechaduri
authors.forename: Kusum
authors.initials: K
authors.lastname: Chawla
authors.forename: Minh
authors.initials: M
authors.lastname: Tran
authors.forename: Xiaomeng
authors.initials: X
authors.lastname: Chai
authors.forename: Cory
authors.initials: C
authors.lastname: Wagg
authors.forename: Mohsen
authors.initials: M
authors.lastname: Ghanefar
authors.forename: Xinghang
authors.initials: X
authors.lastname: Jiang
authors.forename: Marina
authors.initials: M
authors.lastname: Bayeva
authors.forename: Frank
authors.initials: F
authors.lastname: Gonzalez
authors.forename: Gary
authors.initials: G
authors.lastname: Lopaschuk
authors.forename: Hossein
authors.initials: H
authors.lastname: Ardehali
mesh_terms: D000818:Animals; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics* / Q000378:metabolism; D058065:Diabetic Cardiomyopathies / Q000235:genetics* / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism; D005786:Gene Expression Regulation; D055786:Gene Knockout Techniques; D057809:HEK293 Cells; D006801:Humans; D050356:Lipid Metabolism; D018345:Mice, Knockout; D008820:Mice, Obese; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic; D014280:Triglycerides / Q000378:metabolism; D020257:Ventricular Remodeling
chemical_list: C497397:Arnt protein, mouse; D005227:Fatty Acids; D047493:PPAR alpha; D014280:Triglycerides; D051784:Aryl Hydrocarbon Receptor Nuclear Translocator