Glycogen Synthase Kinase 3α Deficiency Attenuates Atherosclerosis and Hepatic Steatosis in High Fat Diet-Fed Low Density Lipoprotein Receptor-Deficient Mice

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.