Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, Beijing 100050, China.
Mol Cell Biochem. 2011 Nov;357(1-2):65-72. doi: 10.1007/s11010-011-0876-4. Epub 2011 May 21.
PTP1B is a negative regulator of insulin signaling pathway. This study investigated the effects of compound CCF06240, a PTP1B inhibitor, on insulin sensitivity and lipid metabolic abnormalities in vivo and in vitro, respectively. The insulin resistant IRM mouse model was induced by HFD. The responses to insulin were determined by OGTT, ITT, and hyperinsulinemic-euglycemic clamp test. The body weight and the levels of serum TC and TG were measured to estimate the lipid metabolism in vivo. Recombinant human GST-PTP1B protein was used to measure the inhibition of CCF06240 on PTP1B activity. The hepatocyte lipid accumulation was induced by high concentrations of FFA and insulin in HepG(2) cells, and evaluated by the Oil Red O method. In IRM mice, the insulin resistance was improved; the body weight and the levels of TC and TG were also reduced by oral CCF06240 administration. In lipid accumulated model cells, CCF06240 was found to reverse the increased PTP1B activity, enhance the insulin-induced tyrosine phosphorylation in insulin signaling pathway, attenuate the FFA-insulin-induced cellular lipid accumulation, and down-regulate the expressions of genes related fatty acid synthesis. These results demonstrated that the PTP1B inhibitor, compound CCF06240, could increase insulin sensitivity through the regulation of insulin signaling pathway, and decrease FFA-insulin-induced hepatocytes lipid accumulation by reducing fatty acid syntheses.
PTP1B 是胰岛素信号通路的负调控因子。本研究分别在体内和体外研究了 PTP1B 抑制剂 CCF06240 对胰岛素敏感性和脂质代谢异常的影响。通过 HFD 诱导胰岛素抵抗（IR）小鼠模型。通过 OGTT、ITT 和高胰岛素-正葡萄糖钳夹试验来确定胰岛素的反应。测量体重和血清 TC 和 TG 水平，以评估体内的脂质代谢。使用重组人 GST-PTP1B 蛋白来测量 CCF06240 对 PTP1B 活性的抑制作用。在 HepG2 细胞中用高浓度的 FFA 和胰岛素诱导肝细胞脂质积累，并通过油红 O 法进行评估。在 IRM 小鼠中，口服 CCF06240 可改善胰岛素抵抗，降低体重和 TC、TG 水平。在脂质积累模型细胞中，CCF06240 可逆转增加的 PTP1B 活性，增强胰岛素信号通路中诱导的酪氨酸磷酸化，减轻 FFA-胰岛素诱导的细胞脂质积累，并下调与脂肪酸合成相关的基因表达。这些结果表明，PTP1B 抑制剂 CCF06240 可通过调节胰岛素信号通路来增加胰岛素敏感性，并通过减少脂肪酸合成来降低 FFA-胰岛素诱导的肝细胞脂质积累。
