Bartels Emil D, Nielsen Jan M, Hellgren Lars I, Ploug Thorkil, Nielsen Lars B
Department of Clinical Biochemistry, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.
PLoS One. 2009;4(4):e5300. doi: 10.1371/journal.pone.0005300. Epub 2009 Apr 23.
Obesity causes lipid accumulation in the heart and may lead to lipotoxic heart disease. Traditionally, the size of the cardiac triglyceride pool is thought to reflect the balance between uptake and beta-oxidation of fatty acids. However, triglycerides can also be exported from cardiomyocytes via secretion of apolipoproteinB-containing (apoB) lipoproteins. Lipoprotein formation depends on expression of microsomal triglyceride transfer protein (MTP); the mouse expresses two isoforms of MTP, A and B. Since many aspects of the link between obesity-induced cardiac disease and cardiac lipid metabolism remain unknown, we investigated how cardiac lipoprotein synthesis affects cardiac expression of triglyceride metabolism-controlling genes, insulin sensitivity, and function in obese mice. Heart-specific ablation of MTP-A in mice using Cre-loxP technology impaired upregulation of MTP expression in response to increased fatty acid availability during fasting and fat feeding. This resulted in cardiac triglyceride accumulation but unaffected cardiac insulin-stimulated glucose uptake. Long-term fat-feeding of male C57Bl/6 mice increased cardiac triglycerides, induced cardiac expression of triglyceride metabolism-controlling genes and attenuated heart function. Abolishing cardiac triglyceride accumulation in fat-fed mice by overexpression of an apoB transgene in the heart prevented the induction of triglyceride metabolism-controlling genes and improved heart function. The results suggest that in obesity, the physiological increase of cardiac MTP expression serves to attenuate cardiac triglyceride accumulation albeit without major effects on cardiac insulin sensitivity. Nevertheless, the data suggest that genetically increased lipoprotein secretion prevents development of obesity-induced lipotoxic heart disease.
肥胖会导致心脏中脂质蓄积，并可能引发脂毒性心脏病。传统观点认为，心脏甘油三酯池的大小反映了脂肪酸摄取与β-氧化之间的平衡。然而，甘油三酯也可通过含载脂蛋白B（apoB）的脂蛋白分泌从心肌细胞中输出。脂蛋白的形成取决于微粒体甘油三酯转运蛋白（MTP）的表达；小鼠表达MTP的两种异构体，即A和B。由于肥胖诱导的心脏病与心脏脂质代谢之间联系的许多方面仍不清楚，我们研究了心脏脂蛋白合成如何影响肥胖小鼠中甘油三酯代谢控制基因的心脏表达、胰岛素敏感性和心脏功能。利用Cre-loxP技术在小鼠中进行心脏特异性MTP-A基因敲除，损害了禁食和高脂喂养期间脂肪酸供应增加时MTP表达的上调。这导致心脏甘油三酯蓄积，但不影响心脏胰岛素刺激的葡萄糖摄取。对雄性C57Bl/6小鼠进行长期高脂喂养会增加心脏甘油三酯，诱导甘油三酯代谢控制基因的心脏表达，并减弱心脏功能。通过在心脏中过表达apoB转基因来消除高脂喂养小鼠的心脏甘油三酯蓄积，可防止甘油三酯代谢控制基因的诱导，并改善心脏功能。结果表明，在肥胖状态下，心脏MTP表达的生理性增加有助于减轻心脏甘油三酯蓄积，尽管对心脏胰岛素敏感性没有重大影响。然而，数据表明，基因上增加的脂蛋白分泌可预防肥胖诱导的脂毒性心脏病的发生。
