title: Glycogen synthase kinase 3α deficiency attenuates atherosclerosis and hepatic steatosis in high fat diet-fed low density lipoprotein receptor-deficient mice.
abstract: 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 < 0.05), compared with 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.
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Nicole S
authors.initials: NS
authors.lastname: Banko
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Cameron S
authors.initials: CS
authors.lastname: McAlpine
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Venegas-Pino
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Preeya
authors.initials: P
authors.lastname: Raja
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Yuanyuan
authors.initials: Y
authors.lastname: Shi
authors.affiliation: Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada.
authors.forename: Mohammad I
authors.initials: MI
authors.lastname: Khan
authors.affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada; Thrombosis and Atherosclerosis Research Institute, McMaster University, Hamilton, Ontario, Canada; Department of Medicine, McMaster University, Hamilton, Ontario, Canada. Electronic address: geoff.werstuck@taari.ca.
authors.forename: Geoff H
authors.initials: GH
authors.lastname: Werstuck
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001835:Body Weight; D059305:Diet, High-Fat; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D005838:Genotype; D038362:Glycogen Synthase Kinase 3 / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D008099:Liver / Q000473:pathology*; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D011973:Receptors, LDL; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; C448021:glycogen synthase kinase 3 alpha