Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis
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Le résumé fourni par la source
BACKGROUND: Individuals with type 1 diabetes (T1D) generally have normal or even higher HDL (high-density lipoprotein)-cholesterol levels than people without diabetes yet are at increased risk for atherosclerotic cardiovascular disease (CVD). Human HDL is a complex mixture of particles that can vary in cholesterol content by >2-fold. To investigate if specific HDL subspecies contribute to the increased atherosclerosis associated with T1D, we created mouse models of T1D that exhibit human-like HDL subspecies. We also measured HDL subspecies and their association with incident CVD in a cohort of people with T1D. METHODS: We generated LDL receptor–deficient ( Ldlr −/− ) mouse models of T1D expressing human APOA1 (apolipoprotein A1). Ldlr −/− APOA1 Tg mice exhibited the main human HDL subspecies. We also generated Ldlr −/− APOA1 Tg T1D mice expressing CETP (cholesteryl ester transfer protein), which had lower concentrations of large HDL subspecies versus mice not expressing CETP. HDL particle concentrations and sizes and proteins involved in lipoprotein metabolism were measured by calibrated differential ion mobility analysis and targeted mass spectrometry in the mouse models of T1D and in a cohort of individuals with T1D. Endothelial transcytosis was analyzed by total internal reflection fluorescence microscopy. RESULTS: Diabetic Ldlr −/− APOA1 Tg mice were severely hyperglycemic and hyperlipidemic and had markedly elevated plasma APOB levels versus nondiabetic littermates but were protected from the proatherogenic effects of diabetes. Diabetic Ldlr −/− APOA1 Tg mice expressing CETP lost the atheroprotective effect and had increased lesion necrotic core areas and APOB accumulation, despite having lower plasma APOB levels. The detrimental effects of low concentrations of larger HDL particles in diabetic mice expressing CETP were not explained by reduced cholesterol efflux. Instead, large HDL was more effective than small HDL in preventing endothelial transcytosis of LDL mediated by scavenger receptor class B type 1. Finally, in humans with T1D, increased concentrations of larger HDL particles relative to APOB100 negatively predicted incident CVD independently of HDL-cholesterol levels. CONCLUSIONS: Our results suggest that the balance between APOB lipoproteins and the larger HDL subspecies contributes to atherosclerosis progression and incident CVD in the setting of T1D and that larger HDLs exert atheroprotective effects on endothelial cells rather than by promoting macrophage cholesterol efflux.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.
- Titre Crossref
- Imbalance of APOB Lipoproteins and Large HDL in Type 1 Diabetes Drives Atherosclerosis
- Date Crossref
- 05/07/2024
- Éditeur
- Ovid Technologies (Wolters Kluwer Health)
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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St. Michael's Hospital Keenan Centre for Biomedical Research pays non établi dans la noticeÉtablissement de santé
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University of Colorado Health pays non établi dans la noticeÉtablissement de santé
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University of Colorado Denver Barbara Davis Center for Diabetes pays non établi dans la noticeUniversité ou école supérieure
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New York University Department of Medicine pays non établi dans la noticeUniversité ou école supérieure
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Defense Information School pays non établi dans la noticeUniversité ou école supérieure
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University of Toronto Interdepartmental Division of Critical Care and the Department of Biochemistry pays non établi dans la noticeUniversité ou école supérieure
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University of Washington Department of Laboratory Medicine and Pathology pays non établi dans la noticeUniversité ou école supérieure
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University of Washington Applied Physics Laboratory pays non établi dans la noticeStructure de recherche
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UW Medicine Diabetes Institute (V.K. Department of Medicine pays non établi dans la noticeStructure de recherche
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Department of Laboratory Medicine and Pathobiology (T.W.W.H. pays non établi dans la noticeStructure de recherche
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Division of Endocrinology pays non établi dans la noticeInstitution
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The Information School (J.O.W.) pays non établi dans la noticeInstitution
Keenan Centre for Biomedical Research — St. Michael's Hospital, University of Colorado Health et Barbara Davis Center for Diabetes — University of Colorado Denver, avec 9 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.