Krishnan Jaya, Suter Marianne, Windak Renata, Krebs Tatiana, Felley Allison, Montessuit Christophe, Tokarska-Schlattner Malgorzata, Aasum Ellen, Bogdanova Anna, Perriard Evelyne, Perriard Jean-Claude, Larsen Terje, Pedrazzini Thierry, Krek Wilhelm
Institute of Cell Biology and Competence Center for Systems Physiology and Metabolic Diseases, ETH Zurich, Zurich, Switzerland.
Cell Metab. 2009 Jun;9(6):512-24. doi: 10.1016/j.cmet.2009.05.005.
Development of cardiac hypertrophy and progression to heart failure entails profound changes in myocardial metabolism, characterized by a switch from fatty acid utilization to glycolysis and lipid accumulation. We report that hypoxia-inducible factor (HIF)1alpha and PPARgamma, key mediators of glycolysis and lipid anabolism, respectively, are jointly upregulated in hypertrophic cardiomyopathy and cooperate to mediate key changes in cardiac metabolism. In response to pathologic stress, HIF1alpha activates glycolytic genes and PPARgamma, whose product, in turn, activates fatty acid uptake and glycerolipid biosynthesis genes. These changes result in increased glycolytic flux and glucose-to-lipid conversion via the glycerol-3-phosphate pathway, apoptosis, and contractile dysfunction. Ventricular deletion of Hif1alpha in mice prevents hypertrophy-induced PPARgamma activation, the consequent metabolic reprogramming, and contractile dysfunction. We propose a model in which activation of the HIF1alpha-PPARgamma axis by pathologic stress underlies key changes in cell metabolism that are characteristic of and contribute to common forms of heart disease.
心肌肥厚的发展以及向心力衰竭的进展会导致心肌代谢发生深刻变化，其特征是从脂肪酸利用转向糖酵解和脂质蓄积。我们报告称，分别作为糖酵解和脂质合成代谢关键介质的缺氧诱导因子（HIF）1α和过氧化物酶体增殖物激活受体（PPAR）γ在肥厚型心肌病中共同上调，并协同介导心脏代谢的关键变化。响应病理应激时，HIF1α激活糖酵解基因和PPARγ，而PPARγ的产物反过来又激活脂肪酸摄取和甘油脂质生物合成基因。这些变化导致糖酵解通量增加，以及通过3-磷酸甘油途径的葡萄糖向脂质转化、细胞凋亡和收缩功能障碍。小鼠心室中Hif1α的缺失可防止肥大诱导的PPARγ激活、随之而来的代谢重编程以及收缩功能障碍。我们提出了一个模型，其中病理应激激活HIF1α-PPARγ轴是细胞代谢关键变化的基础，这些变化是常见心脏病形式的特征并促成这些疾病。
