Metabolomic anatomy of an animal model revealing homeostatic imbalances in dyslipidaemia.
Metabolomics is an emerging technology that reveals homeostatic imbalances in biological systems. Global determination of metabolite concentrations in body fluid and tissues provides novel anatomical aspects of pathological conditions that cannot be obtained from target-specific measurements. Here, we characterised metabolic imbalance in Watanabe heritable hyperlipidaemic rabbits as a model of hypercholesterolaemia. Using a mass spectrometry-based system, we measured a total of 335 metabolites in plasma and tissues (liver, aorta, cardiac muscle, and brain) from WHHL and healthy control rabbits. From the comparison between two metabolomic profiles, pathophysiological features including glutathione and phosphatidylcholine metabolism indicated the occurrence of oxidative stress in several tissues. Especially for the liver, imbalanced purine catabolism shed light on the transcriptional activation of xanthine oxidase, which is thought to act in absorbing or possibly triggering oxidative stress. We also applied this system to assess the therapeutic effects of simvastatin administration. After the treatment, a portion of the metabolomic features in pathological conditions showed alterations suggesting restoration of metabolism to the healthy condition. These changes were considered to be due to the pleiotropic action of statin, including antioxidant effects, rather than its main inhibitory action on cholesterol biosynthesis.
Human Metabolome Technologies, Inc, 246-2 Mizukami, Kakuganji, Tsuruoka, Yamagata 997-0052, Japan.
Takushi
T
Ooga
Hajime
H
Sato
Atsushi
A
Nagashima
Kazunori
K
Sasaki
Masaru
M
Tomita
Tomoyoshi
T
Soga
Yoshiaki
Y
Ohashi
D000818:Animals; D004195:Disease Models, Animal; D050171:Dyslipidemias / Q000503:physiopathology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D050356:Lipid Metabolism / Q000187:drug effects; D008055:Lipids / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D055432:Metabolomics; D018384:Oxidative Stress; D011817:Rabbits; D019821:Simvastatin / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000235:genetics
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008055:Lipids; D019821:Simvastatin; D014969:Xanthine Oxidase