CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients
CDKN2B expression in adipose tissue of familial combined hyperlipidemia patients
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DOI：
10.1194/jlr.m041814
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发表时间：
2013-12-01
影响因子：
6.5
通讯作者：
Shoulders, Carol C.
中科院分区：
文献类型：
--
作者：
Horswell, Stuart D.;Fryer, Lee G. D.;Shoulders, Carol C.
本研究的目的是确定家族性混合性高脂血症 (FCHL) 患者皮下脂肪组织中受到干扰的核心生物过程。 FCHL 和对照微阵列数据集的注释揭示了独特的 FCHL 转录组，其特征是调节五个重叠系统的基因表达变化：细胞骨架、细胞粘附和细胞外基质；囊泡贩运；脂质稳态；以及细胞周期和细胞凋亡。细胞周期抑制剂 CDKN2B 的表达值增加，复制了独立 FCHL 队列的数据。在 3T3-L1 细胞中，CDKN2B 敲低诱导 C/EBP α 表达和脂质积累。 SNP 位点 rs1063192 (C) 上的小等位基因预计会为人类 miRNA-323b-5p 创造完美的种子。 miR-323b-5p 模拟物显着降低内源性 CDKN2B 蛋白水平和携带 rs1063192 C 等位基因的 CDKN2B 3'UTR 荧光素酶报告基因的活性。尽管该等位基因显示出与 MuTHER 脂肪组织数据集中 CDKN2B mRNA 减少相关的暗示证据，但家族研究表明 CDKN2B 表达增加与 FCHL 脂质异常之间的关联是由该基因位点外部因素驱动的。总之，通过对两个单独的 FCHL 脂肪组织转录组的比较注释分析以及随后对 CDKN2B 的关注，我们提出功能失调的脂肪生成是 FCHL 发病机制的一个组成部分。
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 CDKN2B were increased, replicating data from an independent FCHL cohort. In 3T3-L1 cells, CDKN2B knockdown induced C/EBP alpha 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 CDKN2B 3'UTR luciferase reporter carrying the rs1063192 C allele. Although the allele displayed suggestive evidence of association with reduced CDKN2B mRNA in the MuTHER adipose tissue dataset, family studies suggest the association between increased CDKN2B expression 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.