Ueno Masami, Suzuki Jinya, Zenimaru Yasuo, Takahashi Sadao, Koizumi Tsutomu, Noriki Sakon, Yamaguchi Osamu, Otsu Kinya, Shen Wen-Jun, Kraemer Fredric B, Miyamori Isamu
Third Department of Internal Medicine, Faculty of Medical Science, University of Fukui, Fukui, Japan.
Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E1109-18. doi: 10.1152/ajpendo.00016.2008. Epub 2008 Apr 15.
Intracellular lipid accumulation (steatosis) and resultant lipotoxicity are key features of diabetic cardiomyopathy. Since cardiac hormone-sensitive lipase (HSL) is activated in diabetic mice, we sought to explore a pathophysiological function of cardiac HSL in the development of diabetic cardiomyopathy. Transgenic (Tg) mice with heart-specific HSL overexpression were generated, and cardiac histology, function, lipid profile, and gene expressions were analyzed after induction of diabetes by streptozotocin. Electron microscopy showed numerous lipid droplets in wild-type (Wt) hearts after 3 wk of diabetes, whereas Tg mice showed no lipid droplet accumulation. Cardiac content of acylglycerides was increased approximately 50% with diabetes in Wt mice, whereas this was blunted in Tg hearts. Cardiac lipid peroxide content was twofold lower in Tg hearts than in Wt hearts. The mRNA expressions for peroxisome proliferator-activated receptor-alpha, genes for triacylglycerol synthesis, and lipoprotein lipase were increased with diabetes in Wt hearts, whereas this induction was absent in Tg hearts. Expression of genes associated with lipoapoptosis was decreased, whereas antioxidant protein metallothioneins were increased in diabetic Tg hearts. Diabetic Wt hearts showed interstitial fibrosis and increased collagen content. However, Tg hearts displayed no overt fibrosis, concomitant with decreased expression of collagens, transforming growth factor-beta, and matrix metalloproteinase 2. Notably, mortality during the experimental period was approximately twofold lower in diabetic Tg mice compared with Wt mice. In conclusion, since HSL overexpression inhibits cardiac steatosis and fibrosis by apparently hydrolyzing toxic lipid metabolites, cardiac HSL could be a therapeutic target for regulating diabetic cardiomyopathy.
细胞内脂质蓄积（脂肪变性）及由此产生的脂毒性是糖尿病性心肌病的关键特征。由于心脏激素敏感性脂肪酶（HSL）在糖尿病小鼠中被激活，我们试图探究心脏HSL在糖尿病性心肌病发生发展中的病理生理功能。构建了心脏特异性过表达HSL的转基因（Tg）小鼠，并在链脲佐菌素诱导糖尿病后分析其心脏组织学、功能、脂质谱和基因表达。电子显微镜显示，糖尿病3周后野生型（Wt）心脏中有大量脂滴，而Tg小鼠未出现脂滴蓄积。Wt小鼠糖尿病时心脏甘油酯含量增加约50%，而Tg心脏中这种增加不明显。Tg心脏中过氧化脂质含量比Wt心脏低两倍。Wt心脏中过氧化物酶体增殖物激活受体α、三酰甘油合成相关基因和脂蛋白脂肪酶的mRNA表达在糖尿病时增加，而Tg心脏中无此诱导现象。糖尿病Tg心脏中与脂肪凋亡相关的基因表达降低，而抗氧化蛋白金属硫蛋白增加。糖尿病Wt心脏出现间质纤维化且胶原含量增加。然而，Tg心脏未出现明显纤维化，同时胶原、转化生长因子β和基质金属蛋白酶2的表达降低。值得注意的是，实验期间糖尿病Tg小鼠的死亡率比Wt小鼠低约两倍。总之，由于HSL过表达通过明显水解有毒脂质代谢产物抑制心脏脂肪变性和纤维化，心脏HSL可能是调节糖尿病性心肌病的治疗靶点。
