| Autor: |
Horswell, Stuart D., Fryer, Lee G.D., Hutchison, Claire E., Zindrou, Dlear, Speedy, Helen E., Town, Margaret-M., Duncan, Emma J., Sivapackianathan, Rasheeta, Patel, Hetal N., Jones, Emma L., Braithwaite, Adam, Salm, Max P.A., Neuwirth, Claire K.Y., Potter, Elizabeth, Anderson, Jonathan R., Taylor, Kenneth M., Seed, Mary, Betteridge, D. John, Crook, Martin A., Wierzbicki, Anthony S., Scott, James, Naoumova, Rossi P., Shoulders, Carol C. |
| Zdroj: |
Journal of Lipid Research; December 2013, Vol. 54 Issue: 12 p3491-3505, 15p |
| Abstrakt: |
The purpose of this study was to determine the core biological processes perturbed in the subcutaneous adipose tissue of familial combined hyperlipidemia (FCHL) patients. Annotation of FCHL and control microarray datasets revealed a distinctive FCHL transcriptome, characterized by gene expression changes regulating five overlapping systems: the cytoskeleton, cell adhesion and extracellular matrix; vesicular trafficking; lipid homeostasis; and cell cycle and apoptosis. Expression values for the cell-cycle inhibitor CDKN2Bwere increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2Bknockdown induced C/EBPα expression and lipid accumulation. The minor allele at SNP site rs1063192 (C) was predicted to create a perfect seed for the human miRNA-323b-5p. A miR-323b-5p mimic significantly reduced endogenous CDKN2B protein levels and the activity of a CDKN2B3′UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2BmRNA in the MuTHERadipose tissue dataset, family studies suggest the association between increased CDKN2Bexpression and FCHL-lipid abnormalities is driven by factors external to this gene locus. In conclusion, from a comparative annotation analysis of two separate FCHL adipose tissue transcriptomes and a subsequent focus on CDKN2B, we propose that dysfunctional adipogenesis forms an integral part of FCHL pathogenesis. |
| Databáze: |
Supplemental Index |
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