期刊
PHYSIOLOGICAL GENOMICS
卷 41, 期 3, 页码 224-231出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/physiolgenomics.00188.2009
关键词
atherosclerotic mouse model; hypercholesterolemia; metabolomics; systems biology; low-density lipoprotein; apolipoprotein E
资金
- Universiti Teknologi Malaysia
- Royal Society, UK
Cheng K-K, Benson GM, Grimsditch DC, Reid DG, Connor SC, Griffin JL. Metabolomic study of the LDL receptor null mouse fed a high-fat diet reveals profound perturbations in choline metabolism that are shared with ApoE null mice. Physiol Genomics 41: 224-231, 2010. First published March 2, 2010; doi: 10.1152/physiolgenomics. 00188.2009.-Failure to express or expression of dysfunctional low-density lipoprotein receptors (LDLR) causes familial hypercholesterolemia in humans, a disease characterized by elevated blood cholesterol concentrations, xanthomas, and coronary heart disease, providing compelling evidence that high blood cholesterol concentrations cause atherosclerosis. In this study, we used H-1 nuclear magnetic resonance spectroscopy to examine the metabolic profiles of plasma and urine from the LDLR knockout mice. Consistent with previous studies, these mice developed hypercholesterolemia and atherosclerosis when fed a high-fat/cholesterol/cholate-containing diet. In addition, multivariate statistical analysis of the metabolomic data highlighted significant differences in tricarboxylic acid cycle and fatty acid metabolism, as a result of high-fat/cholesterol diet feeding. Our metabolomic study also demonstrates that the effect of high-fat/cholesterol/cholate diet, LDLR gene deficiency, and the diet-genotype interaction caused a significant perturbation in choline metabolism, notably the choline oxidation pathway. Specifically, the loss in the LDLR caused a marked reduction in the urinary excretion of betaine and dimethylglycine, especially when the mice are fed a high-fat/cholesterol/cholate diet. Furthermore, as we demonstrate that these metabolic changes are comparable with those detected in ApoE knockout mice fed the same high-fat/cholesterol/cholate diet they may be useful for monitoring the onset of atherosclerosis across animal models.
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