Wu Rongxue, Chang Hsiang-Chun, Khechaduri Arineh, Chawla Kusum, Tran Minh, Chai Xiaomeng, Wagg Cory, Ghanefar Mohsen, Jiang Xinghang, Bayeva Marina, Gonzalez Frank, Lopaschuk Gary, Ardehali Hossein
J Clin Invest. 2014 Nov;124(11):4795-806. doi: 10.1172/JCI76737. Epub 2014 Oct 20.
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.
2型糖尿病患者常伴有心血管并发症；然而，糖尿病如何导致心脏功能障碍尚不清楚。在小鼠模型中，肝脏或胰腺中编码芳烃核转运体（ARNT，也称为HIF1β）的基因缺失会导致糖尿病表型；然而，ARNT在心脏代谢中的作用尚不清楚。在此，我们确定成年小鼠心脏特异性缺失Arnt会导致心肌病（CM）快速发展，其特征是脂滴积累。与表达ARNT的小鼠心脏相比，对ARNT缺陷心脏的离体分析显示脂肪酸（FA）氧化增加了2倍，同时PPARα及其靶基因的表达也大幅增加。此外，同时缺失Arnt和Ppara可保留心脏功能、提高生存率并完全逆转FA积累表型，表明PPARα介导了Arnt缺失对心脏的有害作用。最后，我们确定ARNT通过与Ppara启动子结合并与HIF2α形成复合物直接调节Ppara表达。总之，这些发现表明ARNT是心肌FA代谢的关键调节因子，其缺失会导致CM并通过PPARα增加甘油三酯积累。
