TLR2/4信号通路在PPARδ改善脂毒性所致肝脏胰岛素抵抗中的作用及其机制研究

Hepatic insulin resistance plays an important role in the pathogenesis of type 2 diabetes. Free fatty acid (FFA) can induce hepatic cellular apoptosis and lead to hepatic cellular insulin resistance by upregulating the expression of Toll-like receptors (TLRs) 2/4 then activating NF-κB and JNK signaling pathways.Our preliminary studies shown that activated peroxisome proliferator-activated receptor δ(PPARδ) in pancreatic β cells ameliorated insulin resistance via protecting β cells from lipotoxic apoptosis. It has been reported that activated PPARδ has an anti-lipotoxic inflammatory role in the liver, we hypothesize that PPARδ may reduce lipotoxic inflammation and lipotoxic apoptosis leading to reduction of insulin resistance in the liver through downregulating TLR2/ 4 signaling pathway. In this project, we will examine TLR2/4 and its downstream inflammatory and apoptotic signal molecules as well as the degree of insulin resistance by means of 1) lipotoxic hepatic cellular model induced by FFA and 2) insulin resistance model induced by high fat from PPARδ knockout（PPARδ-/-）and PPARδ overexpression（PPARδ+/+）mice. Understanding the molecular mechanisms underlying reduction of hepatic insulin resistance by PPARδ regulation of TLR2/4 expression will provide pathophysiological basis for treatments of type 2 diabetes.

肝脏胰岛素抵抗是2型糖尿病发病机制中的重要环节。游离脂肪酸（FFA）可上调肝脏Toll样受体TLR2/4表达，激活NF-κB和JNK信号通路，导致肝细胞凋亡，诱发肝脏胰岛素抵抗。我们的前期研究证实，激活胰腺β细胞过氧化物酶体增殖物激活受体δ（PPARδ）可抑制β细胞脂毒性凋亡，改善胰岛素抵抗。结合文献报道，激活 PPARδ在肝脏中具有抗脂毒性炎症作用。我们假设PPARδ可能通过下调肝脏TLR2/4信号通路来缓解脂毒性炎症及细胞凋亡，从而减轻胰岛素抵抗。本项目拟在敲除PPARδ（PPARδ-/-）和高表达PPARδ（PPARδ+/+）条件下，采用FFA诱导的脂毒性肝细胞模型，及高脂诱导的胰岛素抵抗模型，在细胞及动物水平，检测TLR2/4及下游炎症和凋亡信号分子、胰岛素抵抗程度的变化情况，旨在探索PPARδ调控TLR2/4表达改善肝脏胰岛素抵抗的分子机制，并为治疗2型糖尿病提供理论支持。