Development of hypertrophic cardiomyopathy in perilipin-1 null mice with adipose tissue dysfunction
Development of hypertrophic cardiomyopathy in perilipin-1 null mice with adipose tissue dysfunction
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具有脂肪组织功能障碍的 perilipin-1 缺失小鼠发生肥厚性心肌病
DOI：
10.1093/cvr/cvu214
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发表时间：
2015-01-01
影响因子：
10.8
通讯作者：
Xu, Guoheng
中科院分区：
文献类型：
--
作者：
Liu, Shangxin;Geng, Bin;Xu, Guoheng
Perilipin-1（Pun 1）是脂肪细胞中唯一位于脂滴表面的一种脂蛋白，调节脂肪甘油三酯的储存和水解。Plin 1缺乏主要导致啮齿动物和人类的低脂肪和异常脂解。在这里，我们调查是否脂肪组织功能障碍perilipin-1空（Plin 1（-/-））小鼠有适应不良的后果，心脏和与肥厚型cardiomyopathy.Methods和结果Perilipin-1的脂肪细胞特异性表达，但在心肌细胞中检测不到。Plin 1（-/-）小鼠在组织学上是脂肪营养不良的，具有减少的体脂肪。特别地，Plin 1（-/-）小鼠的脂肪细胞，像肥胖和糖尿病哺乳动物的那些一样，显示出强烈的基础脂解和脂肪酸流出到血浆中。这种脂肪组织功能障碍解释了Plin 1（-/-）小鼠心脏中异位脂质积聚和增强的脂肪酸转运和氧化。过量的脂肪酸β-氧化和脂毒性导致活性氧的过度产生和氧化应激，因为心肌细胞的抗氧化能力降低。这些不良因素损害心肌结构和功能，如肌丝紊乱以及不规则和肿胀的线粒体和嵴破坏。最后，Plin 1-/-小鼠表现出明显的心脏肥大，与肥大和功能障碍的标志基因的表达进行性上调，导致心力衰竭，特别是与左心室舒张功能障碍在20周龄。结论脂肪组织功能障碍可能对心脏产生有害影响，并有助于肥厚型心肌病的发展。脂肪组织功能障碍的Plin 1（-/-）小鼠中的肥厚型心肌病可能模拟并从机制上解释了人类两种典型脂肪组织疾病（脂肪营养不良和肥胖）中发生的心肌病。
Aims Perilipin-1 (Pun 1), exclusively located on the surface of lipid droplets in adipocytes, regulates the storage and hydrolysis of adipose triglycerides. Plin1 deficiency primarily causes low adiposity and aberrant Lipolysis in rodents and humans. Here, we investigated whether adipose tissue dysfunction in perilipin-1 null (Plin1(-/-)) mice has maladaptive consequences for the heart and an association with hypertrophic cardiomyopathy.Methods and results Perilipin-1 was expressed specifically in adipocytes but was undetectable in cardiomyocytes. Plin1(-/-) mice were histologically Lipodystrophic, with reduced body fat Paradoxically, the adipocytes of Plin1(-/-) mice, Like those of obese and diabetic mammals, showed robust basal lipolysis and fatty acid efflux to the plasma. Such adipose tissue dysfunctions accounted for the ectopic lipid accumulation and enhanced fatty acid transport and oxidation in Plin1(-/-) mouse hearts. Excessive fatty acid beta-oxidation and Lipotoxicity induced excessive production of reactive oxygen species and oxidative stress because antioxidative capacity was reduced in cardiomyocytes, These malefactors injured the myocardial structure and function, as evidenced by disorganized myofilaments as well as irregular and swollen mitochondria with disrupted cristae. Finally, Plin1-/- mice showed grossly visible cardiac hypertrophy, with progressively up-regulated expression of hypertrophy and dysfunction marker genes, Leading to heart failure, particularly with left ventricular diastotic dysfunction at 20 weeks of age.Conclusions Adipose tissue dysfunction may have deleterious effects on the heart and contribute to the development of hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy in Plin1(-/-) mice with adipose tissue dysfunction may mimic and mechanistically explain the cardiomyopathies occurring in two typical adipose tissue disorders in humans, lipodystrophy and obesity.