Abstract
Circulating lipid molecules reflect biological processes in the body and, thus, are useful tools for preclinical estimation of the efficacy and safety of newly developed drugs. However, background information on profiles of circulating lipid molecules in preclinical animal models is limited. Therefore, we examined the effects of multiple factors such as sex (fasted male vs. female), age (fasted 10 vs. 30 weeks old), and feeding conditions (feeding vs. fasting, 16 vs. 22 hr fasting, 10 AM vs. 4 PM blood collection), on the global profiles of lipid molecules in plasma from Sprague-Dawley rats by using a lipidomic approach. Our assay platform determined 262 lipid molecules (68 phospholipids, 20 sphingolipids, 138 neutral lipids, and 36 polyunsaturated fatty acids and their metabolites) in rat plasma. Multivariate discriminant analysis (orthogonal partial least squares discriminant analysis) and heat maps of statistically significant lipid molecules revealed that the plasma lipid profiles in rats are predominantly influenced by feeding conditions, followed by sex and age. In addition, the fasting duration (16 vs. 22 hr fasting) or the time of blood collection (10 AM vs. 4 PM blood collection) has limited or no contribution on the profiles of lipid molecules in rat plasma. Our results provide useful, fundamental information for exploring and validating biomarkers in future preclinical studies and may help to establish regulatory standards for such studies.
Highlights
Circulating metabolites are useful tools to diagnose diseases such as lung and gastrointestinal cancer [1,2,3]
Effects of multiple factors on global profiles of lipid molecules in rat plasma To compare the differences caused by multiple factors on the determined 262 lipid molecules, the orthogonal partial least squares discriminant analysis (OPLS-DA) model was applied
Based on overall comparison by OPLS-DA, feeding condition has a predominant role in the global profiles of lipid molecules, followed by sex and age
Summary
Circulating metabolites are useful tools to diagnose diseases such as lung and gastrointestinal cancer [1,2,3]. The advantages of diagnostic applications using circulating metabolites are non- or low-invasiveness, as well as homogeneity between humans and experimental animal models These advantages are shared with the application of circulating metabolites as biomarkers for estimation of the efficacy and safety of newly developed drugs. The phospholipid 18:0/18:1 phosphatidylcholine (PC) acts as a circulating regulator of fatty acid uptake in muscle [8], and ceramides (Cer), a class of sphingolipids, mediate saturated fatty acid-induced insulin resistance [9]. Fatty acid metabolites such as arachidonate metabolites are signaling molecules of inflammatory response [10]. Lipids are potential biomarkers to predict the efficacy and toxicity of newly developed drugs
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