Atherosclerosis Susceptibility Loci Identified From a Strain Intercross of Apolipoprotein E–Deficient Mice via a High-Density Genome Scan

Smith, Jonathan; Bhasin, Jeffrey M.; Baglione, Julie; Settle, Megan; Xu, Yaomin; Barnard, John

doi:10.1161/01.atv.0000201044.33220.5c

Cited by 44 publications

(48 citation statements)

References 17 publications

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“…A role for any of these candidates in pathways regulating food intake has not been established. Alternatively, these results may have relevance to other QTL on mouse Chr 17 for atherosclerosis ( Ath26 ) [47] or for obesity ( Obq4 ) [48] .…”

Section: Discussionmentioning

confidence: 83%

Transcriptional Profiling of Chromosome 17 Quantitative Trait Loci for Carbohydrate and Total Calorie Intake in a Mouse Congenic Strain Reveals Candidate Genes and Pathways

Kumar¹,

Richards²

2008

Lifestyle Genomics

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Background/Aims: The genetic basis for ingestive behaviors is virtually unknown. Quantitative trait loci (QTLs) for carbohydrate and energy intake map to mouse chromosome 17 and were previously confirmed by a congenic strain bearing CAST/Ei (CAST) donor segment on the C57BL/6J (B6) background. Methods: We used microarray technology to facilitate gene identification. Gene expression was compared between the B6.CAST-17 (BC-17) congenic and B6 strains in two diets: (1) chow, and (2) carbohydrate/protein vs. fat/protein. Results: Within the QTL and unique to macronutrient selection, Agpat1 (acylglycerol-3-phosphate O-acyltransferase 1) was differentially expressed in hypothalamus. Irrespective of diet, the gene with the highest fold difference in congenic mice was trefoil factor 3 (Tff3) in liver. Several genes involved in fat metabolism were decreased in carbohydrate-preferring congenic mice, while genes associated with carbohydrate metabolism were increased. In particular, the glyoxalase pathway was enhanced including Glo1, Glo2, and dLDH. Higher expression of Glo1 mRNA in BC-17 congenic mice corresponded to increased protein expression revealed by Western blot, and to higher GLO1 activity in blood. Conclusion: These genes represent new candidates for nutrient intake phenotypes. We propose that increased GLO1 in the BC-17 strain supports its need to protect against dietary oxidants resulting from high carbohydrate intake.

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Section: Discussionmentioning

confidence: 83%

Transcriptional Profiling of Chromosome 17 Quantitative Trait Loci for Carbohydrate and Total Calorie Intake in a Mouse Congenic Strain Reveals Candidate Genes and Pathways

Kumar¹,

Richards²

2008

Lifestyle Genomics

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“…Association studies have not yet been reported (Thaisz et al 2012). Another issue is that in some cases, atherosclerosis QTL have been seen under conditions of extreme hyperlipidemia instigated by using parental strains carrying mutations in lipid transport genes (Dansky et al 2002; Smith et al 2006; Teupser et al 2006; Yang et al 2010). Finally, emphasis has been placed on atherosclerosis susceptibility and little information is available on genes encoding resistance to lesion formation (Nadeau and Topol 2006).…”

Section: Discussionmentioning

confidence: 99%

Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice

et al. 2014

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Metabolic diseases such as obesity and atherosclerosis result from complex interactions between environmental factors and genetic variants. A panel of chromosome substitution strains (CSSs) was developed to characterize genetic and dietary factors contributing to metabolic diseases and other biological traits and biomedical conditions. Our goal here was to identify quantitative trait loci (QTLs) contributing to obesity, energy expenditure and atherosclerosis. Parental strains C57BL/6 and A/J together with a panel of 21 CSSs derived from these progenitors were subjected to chronic feeding of rodent chow and atherosclerotic (females) or diabetogenic (males) test diets, and evaluated for a variety of metabolic phenotypes including several traits unique to this report, namely fat pad weights, energy balance and atherosclerosis. A total of 297 QTLs across 35 traits were discovered, two of which provided significant protection from atherosclerosis, and several dozen QTLs modulated body weight, body composition and circulating lipid levels in females and males. While several QTLs confirmed previous reports, most QTLs were novel. Finally, we applied the CSS quantitative genetic approach to energy balance, and identified three novel QTLs controlling energy expenditure and one QTL modulating food intake. Overall, we identified many new QTLs and phenotyped several novel traits in this mouse model of diet-induced metabolic diseases.

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“…The Apoe-null gene has been transferred into the genetic background of inbred strains of mice. Using aortic root lesions as indicators, the order of decreasing atherosclerosis susceptibility is DBA/2J > C57BL/6 > 129 > AKR/J = BALB/c = C3H/HeJ (39)(40)(41). Apoe deficiency in the FVB background is also relatively resistant to the development of atherosclerosis (42).…”

Section: Genetic Approach To Mediators Of Atherosclerosismentioning

confidence: 99%

ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

Getz

Reardon

2016

Journal of Lipid Research

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Human apoE is found in the plasma associated with VLDL and HDL. It is a 34 kDa protein that is posttranslationally modified, mostly by glycosylation. The mature protein contains 299 amino acids and is encoded on chromosome 19. The gene was first sequenced in 1985 (5). The mouse protein is 70% homologous. apoE is the primary ligand for the removal of chylomicron remnants and intermediate density lipoproteins by the liver, functioning to ligate these particles to the LDL receptor (LDLR) and the LDLR-related protein 1 (LRP-1) (6).The understanding of the physiological role of apoE was greatly enhanced by the study of type III hyperlipoproteinemia. Type III hyperlipoproteinemia presents clinically as hypercholesterolemia and hypertriglyceridemia with the presence of cholesterol-enriched VLDL and a high likelihood of premature ischemic heart disease and peripheral vascular disease, as well as xanthomata, especially palmar xanthomata (7). This abnormal VLDL is the result of impaired clearance of remnant lipoproteins; initially demonstrated by the clearance of injected radiolabeled apoB48-and apoB100-containing lipoproteins in these dyslipidemic patients (8). Indeed, the genetics of type III hyperlipoproteinemia or dysfunctional hyperlipoproteinemia revealed the allelic polymorphism of human apoE, initially reported by Utermann, Hees, and Steinmetz (9). This study identified two allelic forms that were designated as E-N for normal apoE and E-D for dysfunctional apoE, with the E-D isoform prevalent in patients with type III hyperlipoproteinemia. Further study of the genetics of the apoE isoforms identified three common allelic variants, E2 (equivalent to the E-D allele), E3 (equivalent to the E-N allele), and E4, encoding apoE2, apoE3, and apoE4, respectively (10). The allele frequencies are 4-13%, 75-85%, and 14-23% for E2, E3, and E4, respectively. APOE2 homozygotes are found in about 2-5% of the human Abstract ApoE is a multifunctional protein that is expressed by many cell types that influences many aspects of cardiovascular physiology. In humans, there are three major allelic variants that differentially influence lipoprotein metabolism and risk for the development of atherosclerosis. Apoe-deficient mice and human apoE isoform knockin mice, as well as hypomorphic Apoe mice, have significantly contributed to our understanding of the role of apoE in lipoprotein metabolism, monocyte/macrophage biology, and atherosclerosis. This brief history of these mouse models will highlight their contribution to the understanding of the role of apoE in these processes. These Apoe / mice have also been extensively utilized as an atherosensitive platform upon which to assess the impact of modulator genes on the development and regression of atherosclerosis. "A golden age for experimental atherosclerosis dawned when Nobuyo Maeda and Jan Breslow knocked out the Apoe gene in mice" (ref. 1, p. 386). These seminal studies were published in 1992, but were preceded by almost 20 years of experimentation on the structure/function of...

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Atherosclerosis Susceptibility Loci Identified From a Strain Intercross of Apolipoprotein E–Deficient Mice via a High-Density Genome Scan

Cited by 44 publications

References 17 publications

Transcriptional Profiling of Chromosome 17 Quantitative Trait Loci for Carbohydrate and Total Calorie Intake in a Mouse Congenic Strain Reveals Candidate Genes and Pathways

Transcriptional Profiling of Chromosome 17 Quantitative Trait Loci for Carbohydrate and Total Calorie Intake in a Mouse Congenic Strain Reveals Candidate Genes and Pathways

Genetic determinants of atherosclerosis, obesity, and energy balance in consomic mice

ApoE knockout and knockin mice: the history of their contribution to the understanding of atherogenesis

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