Dataset Information

Metabolomics of the interaction between PPAR-alpha and age in the PPAR-alpha-null mouse.

ABSTRACT: Regulation between the fed and fasted states in mammals is partially controlled by peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Expression of the receptor is high in the liver, heart and skeletal muscle, but decreases with age. A combined (1)H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry metabolomic approach has been used to examine metabolism in the liver, heart, skeletal muscle and adipose tissue in PPAR-alpha-null mice and wild-type controls during ageing between 3 and 13 months. For the PPAR-alpha-null mouse, multivariate statistics highlighted hepatic steatosis, reductions in the concentrations of glucose and glycogen in both the liver and muscle tissue, and profound changes in lipid metabolism in each tissue, reflecting known expression targets of the PPAR-alpha receptor. Hepatic glycogen and glucose also decreased with age for both genotypes. These findings indicate the development of age-related hepatic steatosis in the PPAR-alpha-null mouse, with the normal metabolic changes associated with ageing exacerbating changes associated with genotype. Furthermore, the combined metabolomic and multivariate statistics approach provides a robust method for examining the interaction between age and genotype.

SUBMITTER: Atherton HJ

PROVIDER: S-EPMC2683722 | biostudies-literature | 2009

REPOSITORIES: biostudies-literature

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Metabolomics of the interaction between PPAR-alpha and age in the PPAR-alpha-null mouse.

Atherton Helen J HJ Gulston Melanie K MK Bailey Nigel J NJ Cheng Kian-Kai KK Zhang Wen W Clarke Kieran K Griffin Julian L JL

Molecular systems biology 20090407

Regulation between the fed and fasted states in mammals is partially controlled by peroxisome proliferator-activated receptor-alpha (PPAR-alpha). Expression of the receptor is high in the liver, heart and skeletal muscle, but decreases with age. A combined (1)H nuclear magnetic resonance (NMR) spectroscopy and gas chromatography-mass spectrometry metabolomic approach has been used to examine metabolism in the liver, heart, skeletal muscle and adipose tissue in PPAR-alpha-null mice and wild-type ...[more]

PMID: 19357638

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Project description:The peroxisome proliferator-activated receptor alpha (PPARÎ±) is a fatty acid-activated transcription factor that governs a variety of biological processes. Little is known about the role of PPARÎ± in the small intestine. Since this organ is frequently exposed to high levels of PPARÎ± ligands via the diet, we set out to characterize the function of PPARÎ± in small intestine using functional genomics experiments and bioinformatics tools. PPARÎ± was expressed at high levels in both human and murine small intestine. Detailed analyses showed that PPARÎ± was expressed highest in villus cells of proximal jejunum. Microarray analyses of total tissue samples revealed, that in addition to genes involved in fatty acid and triacylglycerol metabolism, transcription factors and enzymes connected to sterol and bile acid metabolism, including FXR and SREBP1, were specifically induced. In contrast, genes involved in cell cycle and differentiation, apoptosis, and host defense were repressed by PPARÎ± activation. Additional analyses showed that intestinal PPARÎ± dependent gene regulation occurred in villus cells. Functional implications of array results were corroborated by morphometric data. The repression of genes involved in proliferation and apoptosis was accompanied by a 22% increase in villus height, and a 34% increase in villus area of wild-type animals treated with WY14643. This is the first report providing a comprehensive overview of processes under control of PPARÎ± in the small intestine. We show that PPARÎ± is an important transcriptional regulator in small intestine, which may be of importance for the development of novel foods and therapies for obesity and inflammatory bowel diseases. Experiment Overall Design: Pure bred wild-type (129S1/SvImJ) and PPARÎ±-null (129S4/SvJae) mice were treated with the synthetic PPARÎ± ligand WY14,643 (0.1% w/w) for 5 days. The complete intestines were then removed and total RNA was isolated. Experiment Overall Design: In total 4 experimental groups were present: wild type mice fed the control diet (AIN93M), wild type mice fed the control diet supplemented with 0.1% w/w WY14,643 for 5 days, PPARÎ± knockout mice fed the control diet, PPARÎ± knockout mice fed the control diet supplemented with 0.1% w/wWY14,643 for 5 days. Experiment Overall Design: RNA of 3 biological replicates was hybridized to Affymetrix 430A arrays. Experiment Overall Design: Five microgram total RNA was labelled according to the ENZO-protocol, fragmented and hybridized according to Affymetrix's protocols.

Dataset Information

Metabolomics of the interaction between PPAR-alpha and age in the PPAR-alpha-null mouse.

Publications

Metabolomics of the interaction between PPAR-alpha and age in the PPAR-alpha-null mouse.

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