Cheng Lihong, Ding Guoliang, Qin Qianhong, Huang Yao, Lewis William, He Nu, Evans Ronald M, Schneider Michael D, Brako Florence A, Xiao Yan, Chen Yuqing E, Yang Qinglin
Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, Georgia 30310, USA.
Nat Med. 2004 Nov;10(11):1245-50. doi: 10.1038/nm1116. Epub 2004 Oct 10.
Fatty acid oxidation (FAO) is a primary energy source for meeting the heart's energy requirements. Peroxisome proliferator-activated receptor-delta (PPAR-delta) may have important roles in FAO. But it remains unclear whether PPAR-delta is required for maintaining basal myocardial FAO. We show that cre-loxP-mediated cardiomyocyte-restricted deletion of PPAR-delta in mice downregulates constitutive expression of key FAO genes and decreases basal myocardial FAO. These mice have cardiac dysfunction, progressive myocardial lipid accumulation, cardiac hypertrophy and congestive heart failure with reduced survival. Thus, chronic myocardial PPAR-delta deficiency leads to lipotoxic cardiomyopathy. Together, our data show that PPAR-delta is a crucial determinant of constitutive myocardial FAO and is necessary to maintain energy balance and normal cardiac function. We suggest that PPAR-delta is a potential therapeutic target in treating lipotoxic cardiomyopathy and other heart diseases.
脂肪酸氧化（FAO）是满足心脏能量需求的主要能量来源。过氧化物酶体增殖物激活受体δ（PPAR-δ）可能在脂肪酸氧化中发挥重要作用。但PPAR-δ是否为维持基础心肌脂肪酸氧化所必需仍不清楚。我们发现，通过cre-loxP介导在小鼠中进行心肌细胞特异性PPAR-δ缺失，可下调关键脂肪酸氧化基因的组成型表达，并降低基础心肌脂肪酸氧化。这些小鼠出现心脏功能障碍、进行性心肌脂质蓄积、心脏肥大和充血性心力衰竭，生存率降低。因此，慢性心肌PPAR-δ缺乏会导致脂毒性心肌病。总之，我们的数据表明PPAR-δ是组成型心肌脂肪酸氧化的关键决定因素，对于维持能量平衡和正常心脏功能是必需的。我们认为PPAR-δ是治疗脂毒性心肌病和其他心脏病的潜在治疗靶点。
