Coort Susan L M, Hasselbaink Danny M, Koonen Debby P Y, Willems Jodil, Coumans Will A, Chabowski Adrian, van der Vusse Ger J, Bonen Arend, Glatz Jan F C, Luiken Joost J F P
Department of Molecular Genetics, Cardiovascular Research Institute Maastricht, Maastricht University, P.O. Box 616, NL-6200 Maastricht, Netherlands.
Diabetes. 2004 Jul;53(7):1655-63. doi: 10.2337/diabetes.53.7.1655.
In obesity, the development of cardiomyopathy is associated with the accumulation of myocardial triacylglycerols (TAGs), possibly stemming from elevation of myocardial long-chain fatty acid (LCFA) uptake. Because LCFA uptake is regulated by insulin and contractions, we examined in cardiac myocytes from lean and obese Zucker rats the effects of insulin and the contraction-mimetic agent oligomycin on the initial rate of LCFA uptake, subcellular distribution of FAT/CD36, and LCFA metabolism. In cardiac myocytes from obese Zucker rats, under basal conditions, FAT/CD36 was relocated to the sarcolemma at the expense of intracellular stores. In addition, the LCFA uptake rate, LCFA esterification rate into TAGs, and the intracellular unesterified LCFA concentration each were significantly increased. All these metabolic processes were normalized by the FAT/CD36 inhibitor sulfo-N-succinimidyloleate, indicating its antidiabetic potential. In cardiac myocytes isolated from lean rats, in vitro administration of insulin induced the translocation of FAT/CD36 to the sarcolemma and stimulated initial rates of LCFA uptake and TAG esterification. In contrast, in myocytes from obese rats, insulin failed to alter the subcellular localization of FAT/CD36 and the rates of LCFA uptake and TAG esterification. In cardiac myocytes from lean and obese animals, oligomycin stimulated the initial rates of LCFA uptake and oxidation, although oligomycin only induced the translocation of FAT/CD36 to the sarcolemma in lean rats. The present results indicate that in cardiac myocytes from obese Zucker rats, a permanent relocation of FAT/CD36 to the sarcolemma is responsible for myocardial TAG accumulation. Furthermore, in vitro these cardiac myocytes, although sensitive to contraction-like stimulation, were completely insensitive to insulin, as the basal conditions in hyperinsulinemic, obese animals resemble the insulin-stimulated condition in lean littermates.
在肥胖状态下，心肌病的发展与心肌三酰甘油（TAGs）的积累有关，这可能源于心肌长链脂肪酸（LCFA）摄取的增加。由于LCFA摄取受胰岛素和收缩的调节，我们在瘦型和肥胖型 Zucker 大鼠的心肌细胞中研究了胰岛素和收缩模拟剂寡霉素对LCFA摄取初始速率、FAT/CD36的亚细胞分布以及LCFA代谢的影响。在肥胖型 Zucker 大鼠的心肌细胞中，在基础条件下，FAT/CD36从细胞内储存部位转移至肌膜。此外，LCFA摄取速率、LCFA酯化生成TAG的速率以及细胞内未酯化LCFA浓度均显著增加。所有这些代谢过程均被FAT/CD36抑制剂磺基-N-琥珀酰亚胺油酸酯恢复正常，表明其具有抗糖尿病潜力。在从瘦型大鼠分离的心肌细胞中，体外给予胰岛素可诱导FAT/CD36转位至肌膜，并刺激LCFA摄取和TAG酯化的初始速率。相比之下，在肥胖大鼠的心肌细胞中，胰岛素未能改变FAT/CD36的亚细胞定位以及LCFA摄取和TAG酯化的速率。在瘦型和肥胖动物的心肌细胞中，寡霉素刺激了LCFA摄取和氧化的初始速率，尽管寡霉素仅在瘦型大鼠中诱导了FAT/CD36转位至肌膜。目前的结果表明，在肥胖型 Zucker 大鼠的心肌细胞中，FAT/CD36永久性转位至肌膜导致了心肌TAG积累。此外，在体外，这些心肌细胞尽管对类似收缩的刺激敏感，但对胰岛素完全不敏感，因为高胰岛素血症肥胖动物的基础状态类似于瘦型同窝动物的胰岛素刺激状态。
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