Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo
Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo
复制标题
DOI：
10.1073/pnas.1311176110
复制
发表时间：
2013-07-30
影响因子：
11.1
通讯作者：
Shulman, Gerald I.
中科院分区：
文献类型：
--
作者：
Galbo, Thomas;Perry, Rachel J.;Shulman, Gerald I.
肝脏胰岛素抵抗是2型糖尿病的主要组成部分，但其发病机制的细胞和分子机制尚不清楚。最近的研究表明，饱和脂肪酸通过激活肝脏中的toll样受体4 （TLR-4）受体来诱导肝脏胰岛素抵抗，而TLR-4受体反过来转录激活肝神经酰胺合成，从而抑制胰岛素信号传导。在这项研究中，我们证明了在TLR-4反义寡核苷酸处理和TLR-4敲除小鼠中，饱和或不饱和脂肪诱导的肝脏胰岛素抵抗并不直接需要TLR-4受体信号传导，神经酰胺积累不依赖于TLR-4信号传导，也不是肝脂肪变性和胰岛素信号传导损伤的主要事件。此外，我们发现饱和脂肪和不饱和脂肪都会导致肝脏中二酰基甘油的积累、PKC ε的激活和胰岛素刺激的IRS-2信号的损伤。这些数据表明饱和脂肪诱导的胰岛素抵抗与TLR-4激活和神经酰胺无关。
Hepatic insulin resistance is a principal component of type 2 diabetes, but the cellular and molecular mechanisms responsible for its pathogenesis remain unknown. Recent studies have suggested that saturated fatty acids induce hepatic insulin resistance through activation of the toll-like receptor 4 (TLR-4) receptor in the liver, which in turn transcriptionally activates hepatic ceramide synthesis leading to inhibition of insulin signaling. In this study, we demonstrate that TLR-4 receptor signaling is not directly required for saturated or unsaturated fat-induced hepatic insulin resistance in both TLR-4 antisense oligonucleotide treated and TLR-4 knockout mice, and that ceramide accumulation is not dependent on TLR-4 signaling or a primary event in hepatic steatosis and impairment of insulin signaling. Further, we show that both saturated and unsaturated fats lead to hepatic accumulation of diacylglycerols, activation of PKC epsilon, and impairment of insulin-stimulated IRS-2 signaling. These data demonstrate that saturated fat-induced insulin resistance is independent of TLR-4 activation and ceramides.