Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease

Zhou, Changcheng; Pridgen, Brian; King, Nakesha; Xu, Jinxian; Breslow, Jan L.

doi:10.1194/jlr.m014092

Cited by 66 publications

(64 citation statements)

References 46 publications

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“…Serum lipids were increased markedly as well compared to LDLR null controls. Arterial wall expression of MCP-1, TNF-␣, and IL-1␤ were also increased (2102), but the contribution of insulin deficiency itself is unclear.…”

Section: Tyrosine Phosphorylation Primarily Provides Docking Sitesmentioning

confidence: 98%

“…Unlike other risk factors, hyperglycemia leads to endothelial dysfunction that is systemic, resulting in both aggravation of atherosclerosis and a microvascular disease that is unique to diabetes. Mouse models of type I diabetes in hyperlipidemic mice clearly show an excess of atherosclerosis but also increased hyperlipidemia which complicates the interpretation of the isolated effect of increase blood glucose (867,2102). In type II diabetes, excess free fatty acid exposure and insulin resistance appear to further exacerbate endothelial dysfunction (2000).…”

Section: E Diabetesmentioning

confidence: 99%

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Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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At least 468 individual genes have been manipulated by molecular methods to study their effects on the initiation, promotion, and progression of atherosclerosis. Most clinicians and many investigators, even in related disciplines, find many of these genes and the related pathways entirely foreign. Medical schools generally do not attempt to incorporate the relevant molecular biology into their curriculum. A number of key signaling pathways are highly relevant to atherogenesis and are presented to provide a context for the gene manipulations summarized herein. The pathways include the following: the insulin receptor (and other receptor tyrosine kinases); Ras and MAPK activation; TNF-␣ and related family members leading to activation of NF-B; effects of reactive oxygen species (ROS) on signaling; endothelial adaptations to flow including G protein-coupled receptor (GPCR) and integrin-related signaling; activation of endothelial and other cells by modified lipoproteins; purinergic signaling; control of leukocyte adhesion to endothelium, migration, and further activation; foam cell formation; and macrophage and vascular smooth muscle cell signaling related to proliferation, efferocytosis, and apoptosis. This review is intended primarily as an introduction to these key signaling pathways. They have become the focus of modern atherosclerosis research and will undoubtedly provide a rich resource for future innovation toward intervention and prevention of the number one cause of death in the modern world.

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Section: Tyrosine Phosphorylation Primarily Provides Docking Sitesmentioning

confidence: 98%

Section: E Diabetesmentioning

confidence: 99%

Molecular Biology of Atherosclerosis

Hopkins

2013

Physiological Reviews

382

344

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“…Lipoproteins fractions were isolated by spinning 60 l of plasma in a TL-100 ultracentrifuge (Beckman Coulter, Brea, CA) at its own density (1.006 g/ml) at 70 000 RPM for 3 hours to harvest the supernatant, and then after adjusting the infranatant with solid KBr to a density of 1.063 g/ml spinning it for 70 000 RPM for 18 hours to harvest the supernatant (40). The cholesterol content of each supernatant and the final infranatant were measured and taken to be very-LDL (VLDL) (Ͻ1.006 g/ml), LDL (1.006 Յ d Յ 1.063 g/ml), and high-density lipoprotein (HDL) (d Ͼ 1.063 g/ml) cholesterol, respectively.…”

Section: Plasma Analysismentioning

confidence: 99%

“…Plasma total cholesterol and triglyceride concentrations were determined enzymatically by colorimetric methods as described previously (Roche; Indianapolis, IN) (24,40). Lipoproteins fractions were isolated by spinning 60 l of plasma in a TL-100 ultracentrifuge (Beckman Coulter, Brea, CA) at its own density (1.006 g/ml) at 70 000 RPM for 3 hours to harvest the supernatant, and then after adjusting the infranatant with solid KBr to a density of 1.063 g/ml spinning it for 70 000 RPM for 18 hours to harvest the supernatant (40).…”

Section: Plasma Analysismentioning

confidence: 99%

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Sui

Helsley

Park

et al. 2015

Molecular Endocrinology

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Recent studies have associated endocrine-disrupting chemical (EDC) exposure with the increased risk of cardiovascular disease in humans, but the underlying mechanisms responsible for these associations remain elusive. Many EDCs have been implicated in activation of the nuclear receptor pregnane X receptor (PXR), which acts as a xenobiotic sensor to regulate xenobiotic metabolism in the liver and intestine. Here we report an important role of intestinal PXR in linking xenobiotic exposure and hyperlipidemia. We identified tributyl citrate (TBC), one of a large group of Food and Drug Administration-approved plasticizers for pharmaceutical or food applications, as a potent and selective PXR agonist. TBC efficiently activated PXR and induced PXR target gene expression in vitro and in vivo. Interestingly, TBC activated intestinal PXR but did not affect hepatic PXR activity. Exposure to TBC increased plasma total cholesterol and atherogenic low-density lipoprotein cholesterol levels in wild-type mice, but not in PXR-deficient mice. TBC-mediated PXR activation stimulated the expression of an essential cholesterol transporter, Niemann-Pick C1-like 1 (NPC1L1), in the intestine. Promoter analysis revealed a DR-4 type of PXR response element in the human NPC1L1 promoter, and TBC promoted PXR recruitment onto the NPC1L1 promoter. Consistently, TBC treatment significantly increased lipid uptake by human and murine intestinal cells and deficiency of PXR inhibited TBC-elicited lipid uptake. These findings provide critical mechanistic insight for understanding the impact of EDC-mediated PXR activation on lipid homeostasis and demonstrate a potential role of PXR in mediating the adverse effects of EDCs on cardiovascular disease risk in humans.

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“…Peritoneal macrophages isolated from wild-type C57BL/6J mice were cultured in medium containing [ 3 H]choleresterol diabetic (6)(7)(8)(9)(10), the effect of diabetes on atherosclerosis in mice with more normal, physiological cholesterol levels has not been investigated. Apolipoprotein E (apoE) is a small circulating protein associated predominantly with VLDL and HDL.…”

Section: Cholesterol Effl Ux Assaymentioning

confidence: 99%

Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation

Johnson

Kim

Knudson

et al. 2013

Journal of Lipid Research

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More than 10% of the United States adult population is estimated to have diabetes ( 1 ), and the leading cause of increased mortality in patients with diabetes is enhanced atherosclerosis ( 2, 3 ). A common cluster of harmful changes to lipoprotein metabolism, including increased plasma VLDL and LDL cholesterol, occurs in type-2 diabetic patients and is characterized by the presence of small, dense LDL particles, low HDL , increased triglycerides, and postprandial lipemia ( 4, 5 ). Serum lipid and lipoprotein levels in patients who have well-controlled type-1 diabetes are generally not higher than those in people without diabetes. However, hypertriglyceridemia and reduced HDL are common in poorly controlled patients, and plasma apoB100 levels, which indicate the number of LDL particles, correlate with glycemic control ( 5 ). This underscores the importance of diabetes-induced changes in lipoprotein composition and distribution as a cardiovascular disease (CVD) risk ( 4, 5 ), but how these relatively small changes in lipid metabolism that occur in the general human population lead to increased diabetic complications of atherosclerosis is not completely understood. Current animal models for atherosclerosis have not been able to address this issue satisfactorily, as they rely on gross lipid abnormalities, such as the lack of LDLR or apoE which cause severe hypercholesterolemia. Although modest increases in atherosclerosis have been observed when these hypercholesterolemic mice are made Abstract Diabetes is a major risk factor for cardiovascular disease. To examine how diabetes interacts with a mildly compromised lipid metabolism, we introduced the diabetogenic Ins2 C96Y/+ (Akita) mutation into mice expressing human apoE4 (E4) combined with either an overexpressing human LDL receptor gene (hLDLR) or the wild-type mouse gene. The hLDLR allele caused 2-fold reductions in plasma HDLcholesterol, plasma apoA1, and hepatic triglyceride secretion. Diabetes increased plasma total cholesterol 1.3-fold and increased apoB48 secretion 3-fold, while reducing triglyceride secretion 2-fold. Consequently, diabetic E4 mice with hLDLR secrete increased numbers of small, cholesterol-enriched, apoB48-containing VLDL, although they have near normal plasma cholesterol (<120 mg/dl). Small foam cell lesions were present in the aortic roots of all diabetic E4 mice with hLDLR that we analyzed at six months of age. None were present in nondiabetic mice or in diabetic mice without hLDLR. Aortic expression of genes affecting leukocyte recruitment and adhesion was enhanced by diabetes. ApoA1 levels, but not diabetes, were strongly correlated with the ability of plasma to effl ux cholesterol from macrophages. We conclude that the diabetes-induced proinfl ammatory changes in the vasculature and the hLDLR-mediated cholesterol accumulation in macrophages synergistically trigger atherosclerosis in mice with human apoE4, although neither alone is suffi cient.

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Hyperglycemic Ins2AkitaLdlr−/− mice show severely elevated lipid levels and increased atherosclerosis: a model of type 1 diabetic macrovascular disease

Cited by 66 publications

References 46 publications

Molecular Biology of Atherosclerosis

Molecular Biology of Atherosclerosis

Intestinal Pregnane X Receptor Links Xenobiotic Exposure and Hypercholesterolemia

Diabetic atherosclerosis in APOE*4 mice: synergy between lipoprotein metabolism and vascular inflammation

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