Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S]
Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the long-term studies required. In an attempt to create a model for studying diabe...
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| Format: | Article |
| Language: | English |
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Elsevier
2011-08-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520369236 |
| _version_ | 1818386570141499392 |
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| author | Changcheng Zhou Brian Pridgen Nakesha King Jinxian Xu Jan L. Breslow |
| author_facet | Changcheng Zhou Brian Pridgen Nakesha King Jinxian Xu Jan L. Breslow |
| author_sort | Changcheng Zhou |
| collection | DOAJ |
| description | Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the long-term studies required. In an attempt to create a model for studying diabetic macrovascular disease, we have generated type 1 diabetic Akita mice lacking the low density lipoprotein receptor (Ins2AkitaLdlr−/−). Ins2AkitaLdlr−/− mice were severely hyperglycemic with impaired glucose tolerance. Compared with Ldlr−/− mice, 20-week-old Ins2AkitaLdlr−/− mice fed a 0.02% cholesterol AIN76a diet showed increased plasma triglyceride and cholesterol levels, and increased aortic root cross-sectional atherosclerotic lesion area [224% (P < 0.001) in males and 30% (P < 0.05) in females]. Microarray and quantitative PCR analyses of livers from Ins2AkitaLdlr−/− mice revealed altered expression of lipid homeostatic genes, including sterol-regulatory element binding protein (Srebp)1, liver X receptor (Lxr)α, Abca1, Cyp7b1, Cyp27a1, and Lpl, along with increased expression of pro-inflammatory cytokine genes, including interleukin (Il)1α, Il1β, Il2, tumor necrosis factor (Tnf)α, and Mcp1. Immunofluorescence staining showed that the expression levels of Mcp1, Tnfα, and Il1β were also increased in the atherosclerotic lesions and artery walls of Ins2AkitaLdlr−/− mice. Thus, the Ins2AkitaLdlr−/− mouse appears to be a promising model for mechanistic studies of type 1 diabetes-accelerated atherosclerosis. |
| first_indexed | 2024-12-14T03:56:09Z |
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| id | doaj.art-a4fe198e3aa44b8b858f2ab1f030dbdb |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-14T03:56:09Z |
| publishDate | 2011-08-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-a4fe198e3aa44b8b858f2ab1f030dbdb2022-12-21T23:18:04ZengElsevierJournal of Lipid Research0022-22752011-08-0152814831493Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S]Changcheng Zhou0Brian Pridgen1Nakesha King2Jinxian Xu3Jan L. Breslow4Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY; Graduate Center for Nutritional Sciences, University of Kentucky, Lexington, KYLaboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NYLaboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NYGraduate Center for Nutritional Sciences, University of Kentucky, Lexington, KYTo whom correspondence should be addressed.; Laboratory of Biochemical Genetics and Metabolism, Rockefeller University, New York, NY; To whom correspondence should be addressed.Accelerated atherosclerosis is the leading cause of death in type 1 diabetes, but the mechanism of type 1 diabetes-accelerated atherosclerosis is not well understood, in part due to the lack of a good animal model for the long-term studies required. In an attempt to create a model for studying diabetic macrovascular disease, we have generated type 1 diabetic Akita mice lacking the low density lipoprotein receptor (Ins2AkitaLdlr−/−). Ins2AkitaLdlr−/− mice were severely hyperglycemic with impaired glucose tolerance. Compared with Ldlr−/− mice, 20-week-old Ins2AkitaLdlr−/− mice fed a 0.02% cholesterol AIN76a diet showed increased plasma triglyceride and cholesterol levels, and increased aortic root cross-sectional atherosclerotic lesion area [224% (P < 0.001) in males and 30% (P < 0.05) in females]. Microarray and quantitative PCR analyses of livers from Ins2AkitaLdlr−/− mice revealed altered expression of lipid homeostatic genes, including sterol-regulatory element binding protein (Srebp)1, liver X receptor (Lxr)α, Abca1, Cyp7b1, Cyp27a1, and Lpl, along with increased expression of pro-inflammatory cytokine genes, including interleukin (Il)1α, Il1β, Il2, tumor necrosis factor (Tnf)α, and Mcp1. Immunofluorescence staining showed that the expression levels of Mcp1, Tnfα, and Il1β were also increased in the atherosclerotic lesions and artery walls of Ins2AkitaLdlr−/− mice. Thus, the Ins2AkitaLdlr−/− mouse appears to be a promising model for mechanistic studies of type 1 diabetes-accelerated atherosclerosis.http://www.sciencedirect.com/science/article/pii/S0022227520369236type 1 diabeteshyperglycemiahyperlipidemiaAkita mouseLdlr knockout mouse |
| spellingShingle | Changcheng Zhou Brian Pridgen Nakesha King Jinxian Xu Jan L. Breslow Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S] Journal of Lipid Research type 1 diabetes hyperglycemia hyperlipidemia Akita mouse Ldlr knockout mouse |
| title | Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S] |
| title_full | Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S] |
| title_fullStr | Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S] |
| title_full_unstemmed | Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S] |
| title_short | Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease[S] |
| title_sort | hyperglycemic ins2akitaldlr mice show severely elevated lipid levels and increased atherosclerosis a model of type 1 diabetic macrovascular disease s |
| topic | type 1 diabetes hyperglycemia hyperlipidemia Akita mouse Ldlr knockout mouse |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520369236 |
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