Section of Endocrinology, Department of Internal Medicine, School of Medicine, Yale University, New Haven, Connecticut, USA.
Am J Physiol Heart Circ Physiol. 2012 Sep 15;303(6):H732-42. doi: 10.1152/ajpheart.00948.2011. Epub 2012 Jul 27.
Toll-like receptor (TLR)4 regulates inflammation and metabolism and has been linked to the pathogenesis of heart disease. TLR4 is upregulated in diabetic cardiomyocytes, and we examined the role of TLR4 in modulating cardiac fatty acid (FA) metabolism and the pathogenesis of diabetic heart disease in nonobese diabetic (NOD) mice. Both wild-type (WT) NOD and TLR4-deficient NOD animals had increased plasma triglyceride levels after the onset of diabetes. However, by comparison, TLR4-deficient NOD mouse hearts had lower triglyceride accumulation in the early stages of diabetes, which was associated with a reduction in myeloid differentiation primary response gene (88) (MyD88), phosphorylation of p38 MAPK (phospho-p38), lipoprotein lipase (LPL), and JNK levels but increased phospho-AMP-activated protein kinase (AMPK). Oleic acid treatment in H9C2 cardiomyocytes also led to cellular lipid accumulation, which was attenuated by TLR4 small interfering RNA. TLR4 deficiency in the cells decreased FA-induced augmentation of MyD88, phospho-p38, and LPL, suggesting that TLR4 may modulate FA-induced lipid metabolism in cardiomyocytes. In addition, although cardiac function was impaired in both diabetic WT NOD and TLR4-deficient NOD animals compared with control nondiabetic mice, this deficit was less in the diabetic TLR4-deficient NOD mice, which had greater ejection fraction, greater fractional shortening, and increased left ventricular developed pressure in the early stages after the development of diabetes compared with their diabetic WT NOD counterparts. Thus, we conclude that TLR4 plays a role in regulating lipid accumulation in cardiac muscle after the onset of type 1 diabetes, which may contribute to cardiac dysfunction.
Toll 样受体（TLR）4 调节炎症和代谢，与心脏病的发病机制有关。糖尿病心肌细胞中 TLR4 上调，我们研究了 TLR4 在调节心脏脂肪酸（FA）代谢和非肥胖型糖尿病（NOD）小鼠糖尿病性心脏病发病机制中的作用。WT NOD 和 TLR4 缺陷型 NOD 动物在糖尿病发病后血浆甘油三酯水平均升高。然而，相比之下，TLR4 缺陷型 NOD 小鼠心脏在糖尿病早期的甘油三酯积累较低，这与髓样分化初级反应基因（88）（MyD88）、磷酸化 p38MAPK（磷酸化 p38）、脂蛋白脂肪酶（LPL）和 JNK 水平降低，但磷酸化 AMP 激活的蛋白激酶（AMPK）增加有关。油酸处理 H9C2 心肌细胞也导致细胞脂质积累，TLR4 小干扰 RNA 可减轻这种积累。细胞中的 TLR4 缺陷降低了 FA 诱导的 MyD88、磷酸化 p38 和 LPL 的增强，表明 TLR4 可能调节心肌细胞中 FA 诱导的脂质代谢。此外，尽管与对照非糖尿病小鼠相比，糖尿病 WT NOD 和 TLR4 缺陷型 NOD 动物的心脏功能均受损，但在糖尿病 TLR4 缺陷型 NOD 小鼠中，这种缺陷较小，这些小鼠在糖尿病发病后的早期阶段具有更高的射血分数、更大的缩短分数和增加的左心室发展压。因此，我们得出结论，TLR4 在 1 型糖尿病发病后调节心脏肌肉中的脂质积累中起作用，这可能导致心脏功能障碍。
