title: PTP1B inhibitor improves both insulin resistance and lipid abnormalities in vivo and in vitro.
abstract: 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.
authors: Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences & Perking Union Medical College, Beijing 100050, China.
authors: Yi-ming
authors: YM
authors: Ma
authors: Rong-ya
authors: RY
authors: Tao
authors: Qian
authors: Q
authors: Liu
authors: Juan
authors: J
authors: Li
authors: Jin-ying
authors: JY
authors: Tian
authors: Xiao-lin
authors: XL
authors: Zhang
authors: Zhi-yan
authors: ZY
authors: Xiao
authors: Fei
authors: F
authors: Ye
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