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) 3α/β in the activation of pro-atherogenic pathways and the accelerated development of atherosclerosis. By using a mouse model, we examined the role of GSK3α in the development and progression of accelerated atherosclerosis. We crossed Gsk3a /GSK3α-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. GSK3α deficiency had no detectible effect on any measured parameters in chow-fed mice. High-fat–diet fed Ldlr −/− mice that were deficient for GSK3α had significantly less hepatic lipid accumulation and smaller atherosclerotic lesions (60% smaller in Ldlr −/− ;Gsk3a +/− mice, 80% smaller in Ldlr −/− ;Gsk3a −/− mice; P Ldlr −/− ; Gsk3a +/+ controls. GSK3α 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 GSK3α/β inhibitor CT99021. Together, these results suggest that GSK3α plays a pro-atherogenic role, possibly by mediating the effects of endoplasmic reticulum stress in the activation of pro-atherogenic pathways.