Title
Integrative Biological Analysis of the APOE*3-Leiden Transgenic Mouse
Author
Clish, C.B.
Davidov, E.
Oresic, M.
Plasterer, T.N.
Lavine, G.
Londo, T.
Meys, M.
Snell, P.
Stochaj, W.
Adourian, A.
Zhang, X.
Morel, N.
Neumann, E.
Verheij, E.
Vogels, J.T.W.E.
Havekes, L.M.
Afeyan, N.
Regnier, F.
van der Greef, J.
Naylor, S.
TNO Preventie en Gezondheid
Publication year
2004
Abstract
Integrative (or systems biology) is a new approach to analyzing biological entities as integrated systems of genetic, genomic, protein, metabolite, cellular, and pathway events that are in flux and interdependent. Here, we demonstrate the application of intregrative biological analysis to a mammalian disease model, the apolipoprotein E3-Leiden (APO*E3) transgenic mouse. Mice selected for the study were fed a normal chow diet and sacrificed at 9 weeks of age-conditions under which they develop only mild type I and II atherosclerotic lesions. Hepatic mRNA expression analysis showed a 25% decrease in APO A1 and a 43% increase in liver fatty acid binding protein expression between transgenic and wild type control mice, while there was no change in PPAR-alpha expression. On-line high performance liquid chromatography-mass spectrometry quantitative profiling of tryptic digests of soluble liver proteins and liver lipids, coupled with principle component analysis, enabled rapid identification of early protein and metabolite markers of disease pathology. These included a 44% increase in L-FABP in transgenic animals compared to controls, as well as an increase in triglycerides and select bioactive lysophosphatidylcholine species. A correlation analysis of identified genes, proteins, and lipids was used to construct an interaction network. Taken together, these results indicate that integrative biology is a powerful tool for rapid identification of early markers and key components of pathophysiologic processes, and constitute the first application of this approach to a mammalian system.
Subject
Biology Pharmacology
Analytical research
Biomedical research
DNA
Fatty acid binding protein
Lipid
Liver protein
Lysophosphatidylcholine
Messenger RNA
Peroxisome proliferator activated receptor alpha
Protein
Triacylglycerol
Animal model
Animal tissue
Controlled study
Gene
Gene expression
High performance liquid chromatography
Mass spectrometry
Mouse
Nonhuman
Principal component analysis
Transgenic mouse
Animals
Apolipoprotein E3
Apolipoproteins E
Arteriosclerosis
Carrier Proteins
Chromatography, High Pressure Liquid
Chromatography, Liquid
Fatty Acid-Binding Proteins
Genome
Humans
Lipid Metabolism
Liver
Lysophosphatidylcholines
Mass Spectrometry
Mice
Mice, Transgenic
Models, Biological
Multivariate Analysis
Oligonucleotide Array Sequence Analysis
Receptors, Cytoplasmic and Nuclear
RNA
RNA, Messenger
Transcription Factors
Trypsin
Animalia
Mammalia
Mus musculus
To reference this document use:
http://resolver.tudelft.nl/uuid:ddbd86fa-20ed-4642-bead-1d2fa9579f3a
DOI
https://doi.org/10.1089/153623104773547453
TNO identifier
237717
ISSN
1536-2310
Source
OMICS A Journal of Integrative Biology, 8 (1), 3-13
Document type
article