A fat heart

Patients with type 2 diabetes often develop cardiac complications, such as coronary heart disease and heart failure. It is not clear how cardiac dysfunction develops as a result of diabetes, though several mechanisms have been proposed. In murine models, loss of the transcription factor ARNT in the liver or pancreas results in diabetic phenotypes, and ARNT levels are reduced patient liver and pancreas samples. Rongxue Wu and colleagues at Northwestern University used a murine model to evaluate the effects of ARNT deficiency in the heart. Cardiac-specific deletion of Arnt in adult mice resulted in a cardiomyopathy characterized by accumulation of lipid droplets. ARNT-deficient hearts exhibited increased fatty acid oxidation and expression of PPARα, a transcription factor associated with hypertension. Compared to mice lacking ARNT alone, mice deficient for both ARNT and PPARα had improved survival, normal cardiac function, and no evident fatty acid accumulation in the heart, indicating that PPARα mediates the adverse effects of Arnt deletion. The results of this study demonstrate that reduced ARNT in the heart results in PPARα activation and subsequent fatty acid accumulation and provide a potential target for reducing cardiac lipotoxicity. The accompanying electron micrograph of an ARNT-deficient murine heart shows the accumulation of lipid droplets (electron-lucent areas).

 

Published October 20, 2014, by Corinne Williams

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Cardiac-specific ablation of ARNT leads to lipotoxicity and cardiomyopathy
Rongxue Wu, … , Gary Lopaschuk, Hossein Ardehali
Rongxue Wu, … , Gary Lopaschuk, Hossein Ardehali
Published October 20, 2014
Citation Information: J Clin Invest. 2014;124(11):4795-4806. https://doi.org/10.1172/JCI76737.
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Research Article Cardiology

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

Rongxue Wu, Hsiang-Chun Chang, Arineh Khechaduri, Kusum Chawla, Minh Tran, Xiaomeng Chai, Cory Wagg, Mohsen Ghanefar, Xinghang Jiang, Marina Bayeva, Frank Gonzalez, Gary Lopaschuk, Hossein Ardehali

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