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.
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 (1)H 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.
Cheng
Kian-Kai
KK
Department of Biochemistry.
Benson
G Martin
GM
Grimsditch
David C
DC
Reid
David G
DG
Connor
Susan C
SC
Griffin
Julian L
JL
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism; D002784:Cholesterol / Q000097:blood; D002794:Choline / Q000378:metabolism*; D030541:Databases, Genetic; D004032:Diet; D059305:Diet, High-Fat; D016002:Discriminant Analysis; D005260:Female; D005838:Genotype; D006937:Hypercholesterolemia / Q000097:blood / Q000378:metabolism; D016018:Least-Squares Analysis; D055432:Metabolomics / Q000379:methods*; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008954:Models, Biological; D066244:Proton Magnetic Resonance Spectroscopy; D011973:Receptors, LDL / Q000172:deficiency* / Q000378:metabolism
D001057:Apolipoproteins E; D011973:Receptors, LDL; D002784:Cholesterol; D002794:Choline