Abstract
Comprehensive lipidomic profiling in three different brain tissues (cortex, hippocampus, and hypothalamus) of mouse with p53 deficiency was performed by nanoflow liquid chromatography-tandem mass spectrometry (nLC-MS/MS) and the profile was compared with that of the wild type. p53 gene is a well-known tumour suppressor that prevents genome mutations that can cause cancers. More than 300 lipids (among 455 identified species), including phospholipids (PLs), sphingolipids, ceramides (Cers), and triacylglycerols (TAGs) were quantitatively analysed by selective reaction monitoring (SRM) of nanoflow ultrahigh performance liquid chromatography-electrospray ionization-tandem mass spectrometry (nUPLC-ESI-MS/MS). Among the three different neural tissues, hypothalamus demonstrated the most evident lipid profile changes upon p53 knockout. Alterations of PLs containing acyl chains of docosahexaenoic acid and arachidonic acid (highly enriched polyunsaturated fatty acids in the nervous system) were examined in relation to cell apoptosis upon p53 knockout. Comparison between sphingomyelins (SMs) and Cers showed that the conversion of SM to Cer did not effectively progress in the hypothalamus, resulting in the accumulation of SMs, possibly due to the inhibition of apoptosis caused by the lack of p53. Furthermore, TAGs were considerably decreased only in the hypothalamus, indicative of lipolysis that led to substantial weight loss of adipose tissue and muscles.
Highlights
Among diverse genetic mutations found in different types of cancers, the mutation in the p53 gene, known as the “tumour suppressor gene”, is the most frequent[9,10]
Non-targeted global search of lipids from different tissues was performed by determining the structure of individual lipids from collision-induced dissociation (CID) experiments using nanoflow liquid chromatography-electrospray ionization-tandem mass spectrometry
Base peak chromatograms (BPCs) of cortex, hippocampus, and hypothalamus from wild type (WT) and p53 knockout (p53 KO) mice obtained in negative ion mode are shown in Supplementary Fig. S1
Summary
Among diverse genetic mutations found in different types of cancers, the mutation in the p53 gene, known as the “tumour suppressor gene”, is the most frequent[9,10]. In most cases of cancer, tumour development accompanies metabolic transformation, i.e., the change of the preferred energy production route from oxidative phosphorylation to glycolysis, resulting in limited oxygen supply followed by generation of considerable amount of reactive oxygen species This metabolic transformation could activate the role of p53 through the activation of various p53-stimulating enzymes[18,19]. It is important to elucidate the functions of p53 in brain lipidomics with respect to the occurrence of glioma It is well-known that active cell-to-cell signalling takes place in the brain and that the brain controls the homeostasis of the whole biological system[20,21]. Lipid distribution and relative amount of the lipids present in each type of brain tissue were evaluated and relative changes in individual lipids between wild type (WT) and p53 knockout (p53 KO) mice were statistically examined to elucidate the relationship between the functions of p53 and neural lipids
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