Anti-GSK3A monoclonal antibody, clone 7H3G3

Studies have implicated signaling through glycogen synthase kinase (GSK) 3 alpha/beta in the activation of proatherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3 alpha in the development and progression of accelerated atherosclerosis. We crossed Gsk3a/GSK3 alpha-knockout mice with low-density lipoprotein receptor (Ldlr) knockout mice. Five-week-old Ldlr(-/-);Gsk3a(+)/(+), Ldlr(-/-);Gsk3a(+/-), and Ldlr(-/-);Gsk3a(-/-) mice were fed a chow diet or a high-fat diet for 10 weeks and then sacrificed. GSK3 alpha deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat diet fed Ldlr(-/-) mice that were deficient for GSK3 alpha had significantly less hepatic lipid accumulation and smaller atherosclerotic Lesions (60% smaller in Ldlr(-/-); Gsk3a(+/-) mice, 80% smaller in Ldlr(-/-);Gsk3a(-/-) mice; P < 0.05), compared with Ldlr(-/-);Gsk3a(+/+) controls. GSK3 alpha deficiency was associated with a significant increase in plasma IL-10 concentration and IL-10 expression in isolated macrophages. A twofold to threefold enhancement in endoplasmic reticulum stress-induced IL-10 expression was observed in Thp-1 derived macrophages that were pretreated with the GSK3 alpha/beta inhibitor CT99021. Together, these results suggest that GSK3 alpha plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways.

Nonalcoholic fatty liver disease and cirrhosis are strongly associated with insulin resistance and glucose intolerance. To date, the influence of metformin on glycogen synthesis in the liver is controversial. Limited studies have evaluated the effect of metformin on hepatic insulin signaling pathway in vivo. In this study, an insulin-resistant rat model of nonalcoholic steatohepatitis and cirrhosis was developed by high-fat and high-sucrose diet feeding in combination with subcutaneous injection of carbon tetrachloride. Liver tissues of the model rats were featured with severe steatosis and cirrhosis, accompanied by impaired liver function and antioxidant capacity. The glucose tolerance was impaired, and the index of insulin resistance was increased significantly compared with the control. The content of hepatic glycogen was dramatically decreased. The expression of insulin receptor beta (IR beta); phosphorylations of IR beta, insulin receptor substrate 2 (IRS2), and Akt; and activities of phosphatidylinositol 3-kinase (PI3K) and glycogen synthase (GS) in the liver were significantly decreased, whereas the activities of glycogen synthase kinase 3 alpha (GSK3 alpha) and glycogen phosphorylase a (GPa) were increased. Metformin treatment remarkably improved liver function, alleviated lipid peroxidation and histological damages of the liver, and ameliorated glucose intolerance and insulin resistance. Metfromin also significantly upregulated the expression of IR beta; increased the phosphorylations of IR beta, IRS2, and Akt; increased the activities of PI3K and GS; and decreased GSK3a and GPa activities. In conclusion, our study suggests that metformin upregulates IR beta expression and the downstream IRS2/PI3K/Akt signaling transduction, therefore, to increase hepatic glycogen storage and improve insulin resistance. These actions may be attributed to the improved liver histological alterations by metformin.