Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Gene expression profiling of GPR86 (P2RY13) KO mice

ABSTRACT: The purinergic receptor P2Y13 (P2RY13) has been shown to play a role in the uptake of holo-HDL particles in in vitro hepatocyte experiments. In order to determine the role of P2Y13 in lipoprotein metabolism in vivo, we ablated the expression of this gene in mice and found that P2Y13 knockout mice have lower plasma HDL (17%) and LDL (27%) levels as well as lower fecal concentrations of neutral sterols. In addition, significant decreases were detected in serum levels of fatty acids, glycerol and triglycerides in P2Y13 knockout mice. mRNA profiling analyses showed that ablation of P2Y13 affects hepatic gene expression in a gender-specific manner. Non-supervised agglomerative cluster analysis showed that expression changes in mice with the same genotype (KO or WT) cluster together and that distinct gene expression clusters can be observed for males and females. Subsequent gene set enrichment analysis showed increased expression of cholesterol and fatty acid biosynthesis genes, while fatty acid beta-oxidation genes were significantly decreased. Liver gene signatures also identified changes in SREBP-regulated and PPARgamma-regulated transcript levels. Differential gene expression upon P2RY13 gene ablation. Livers were isolated from male and female wildtype and P2RY13 knockout mice (6 per gender/genotype group, except for 5 per male/WT group). Isolated RNA was subjected to microarray analyses. The results of a one-way ANOVA analysis (p<0.05) showed 3471 transcripts whose relative expression changes were more than 20%.

ORGANISM(S): Mus musculus

SUBMITTER: Oscar Puig

PROVIDER: E-GEOD-20920 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Altered lipoprotein metabolism in P2Y(13) knockout mice.

Blom Daniël D Yamin Ting-Ting TT Champy Marie-France MF Selloum Mohammed M Bedu Elodie E Carballo-Jane Ester E Gerckens Lynn L Luell Silvi S Meurer Roger R Chin Jayne J Mudgett John J Puig Oscar O

Biochimica et biophysica acta 20100915 12

The purinergic receptor P2Y(13) has been shown to play a role in the uptake of holo-HDL particles in in vitro hepatocyte experiments. In order to determine the role of P2Y(13) in lipoprotein metabolism in vivo, we ablated the expression of this gene in mice. Here we show that P2Y(13) knockout mice have lower fecal concentrations of neutral sterols (-27%±2.1% in males) as well as small decreases in plasma HDL (-13.1%±3.2% in males; -17.5%±4.0% in females) levels. In addition, significant decrease ...[more]

PMID: 20817122

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Project description:The sterol regulatory element binding proteins (SREBPs) are transcription factors that govern cholesterol and fatty acid metabolism. Owing to their central role in controlling hepatic lipid and lipoprotein metabolism their activity is tightly coordinated, and accordingly dysregulation of the SREBP pathway is associated with development of dyslipidemia and non-alcoholic fatty liver disease. Using a suite of genome-wide genetic screens we have recently identified SPRING (C12ORF49) as a novel post-transcriptional regulator of SREBP activation in vitro. Our previous work demonstrated that constitutive ablation of Spring in mice is embryonically lethal. Here we show that inducible global deletion of Spring is also untolerated, and therefore to interrogate the physiological role of SPRING in controlling hepatic lipid metabolism we developed liver-specific Spring knockout mice (LKO). Liver transcriptomics and proteomics analysis revealed severely attenuated SREBP signaling in livers and in hepatocytes of LKO mice, which was associated with marked effects on both plasma and hepatic lipid levels. In plasma, total cholesterol levels were dramatically reduced in both male and female LKO mice, apparent in both the LDL and HDL fractions, while triglyceride levels remained largely unaffected. In liver, loss of Spring diminished cholesterol and triglyceride biosynthesis resulting in decreased hepatic cholesterol and triglyceride content. This coincided with reduced secretion of VLDL into the circulation. Consistent with diminished hepatic de novo lipogenesis, LKO mice were protected from developing hepatosteatosis when challenged with a fructose-rich diet. Supporting the significance of our findings in mice, we identified common and rare SPRING genetic variants that are strongly associated with circulating HDL-c and ApoA1 levels in humans. Collectively, our study positions SPRING as a core component of hepatic SREBP signaling, and consequently of systemic lipid metabolism in mice and humans.

Dataset Information

Gene expression profiling of GPR86 (P2RY13) KO mice

Publications

Altered lipoprotein metabolism in P2Y(13) knockout mice.

Similar Datasets

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