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Effects of atherogenic diet on hepatic gene expression across mouse strains.

ABSTRACT: Diets high in fat and cholesterol are associated with increased obesity and metabolic disease in mice and humans. To study the molecular basis of the metabolic response to dietary fat, 10 inbred strains of mice were fed atherogenic high-fat and control low-fat diets. Liver gene expression and whole animal phenotypes were measured and analyzed in both sexes. The effects of diet, strain, and sex on gene expression were determined irrespective of complex processes, such as feedback mechanisms, that could have mediated the genomic responses. Global gene expression analyses demonstrated that animals of the same strain and sex have similar transcriptional profiles on a low-fat diet, but strains may show considerable variability in response to high-fat diet. Functional profiling indicated that high-fat feeding induced genes in the immune response, indicating liver damage, and repressed cholesterol biosynthesis. The physiological significance of the transcriptional changes was confirmed by a correlation analysis of transcript levels with whole animal phenotypes. The results found here were used to confirm a previously identified quantitative trait locus on chromosome 17 identified in males fed a high-fat diet in two crosses, PERA x DBA/2 and PERA x I/Ln. The gene expression data and phenotype data have been made publicly available as an online tool for exploring the effects of atherogenic diet in inbred mouse strains (http://cgd-array.jax.org/DietStrainSurvey).

SUBMITTER: Shockley KR

PROVIDER: S-EPMC2789673 | biostudies-literature | 2009 Nov

REPOSITORIES: biostudies-literature

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Effects of atherogenic diet on hepatic gene expression across mouse strains.

Shockley Keith R KR Witmer David D Burgess-Herbert Sarah L SL Paigen Beverly B Churchill Gary A GA

Physiological genomics 20090811 3

Diets high in fat and cholesterol are associated with increased obesity and metabolic disease in mice and humans. To study the molecular basis of the metabolic response to dietary fat, 10 inbred strains of mice were fed atherogenic high-fat and control low-fat diets. Liver gene expression and whole animal phenotypes were measured and analyzed in both sexes. The effects of diet, strain, and sex on gene expression were determined irrespective of complex processes, such as feedback mechanisms, that ...[more]

PMID: 19671657

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Project description:ObjectivePseudoxanthoma elasticum (PXE) is a multisystem heritable disorder caused by mutations in the Abcc6 gene. The disease is characterized by ectopic mineralization of the skin, eyes, and arterial blood vessels. Previous studies have suggested that cardiovascular complications in patients with PXE are caused in part by premature atherosclerosis. The aim of this study is to determine the effect of an atherogenic diet on ectopic mineralization.MethodsWe used Abcc6 tm1JfK mice (Abcc6 -/- mice) as an established preclinical model of PXE. The offspring at age of 4 weeks were divided into two groups and fed the standard control laboratory diet (control group) and the atherogenic diet. Serum lipid profiles and bile acids were measured, and steatosis and tissue mineralization were evaluated by histopathologic analysis and chemical calcium quantification assay, respectively.ResultsAfter 50-58 weeks of feeding an atherogenic diet, the concentrations of total cholesterol, low-density lipoprotein/very-low-density lipoprotein cholesterol, and bile acids were significantly higher in the Abcc6 -/- mice on the atherogenic diet (180.9 ± 14.8 g/L, 145.9 ± 12.9 g/L, and 9.7 ± 1.4 μmol/L, respectively) than in Abcc6 -/- mice on a control diet (85.2 ± 4.8 g/L, 25.1 ± 5.5 g/L, and 3.3 ± 0.5 μmol/L, respectively) (P < 0.001). Hypercholesterolemia was accompanied by extensive lipid accumulation in the liver and aorta, a characteristic feature of steatosis. The direct calcium assay demonstrated significantly increased mineralization of the muzzle skin containing the dermal sheath of vibrissae (57.2 ± 4.4 μmol Ca/gram tissue on the atherogenic diet and 43.9 ± 2.2 μmol Ca/gram tissue on control diet; P < 0.01), a reproducible biomarker of the ectopic mineralization process in these mice. An increased frequency of mineralization was also observed in the kidneys and eyes of mice on the atherogenic diet (P < 0.01).ConclusionThese observations suggest that the atherogenic diet caused hypercholesterolemia and accelerated ectopic mineralization in the Abcc6 -/- mice. Our findings have clinical implications for patients with PXE, a currently intractable disorder with considerable morbidity and occasional mortality.

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Effects of atherogenic diet on hepatic gene expression across mouse strains.

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Effects of atherogenic diet on hepatic gene expression across mouse strains.

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