Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, 04103, Leipzig, Germany.
German Diabetes Center Leipzig, University of Leipzig, 04103, Leipzig, Germany.
Int J Obes (Lond). 2019 Apr;43(4):821-831. doi: 10.1038/s41366-018-0123-0. Epub 2018 Jun 18.
Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue. The Repin1 resides within a quantitative trait locus (QTL) for body weight and triglyceride levels in the rat, and its hepatic deletion in mice results in improved insulin sensitivity and lower body weight. Here, we analyzed whether genetic variation within the Repin1 affects parameters of glucose and lipid metabolism.
We sequenced REPIN1 in 48 non-related Caucasian subjects. We discovered a 12 base pair deletion (12 bp del; rs3832490), which was subsequently genotyped in two well-characterized cohorts (N = 3013) to test for associations with metabolic traits. Functional consequences of the variant were investigated in HepG2 cells in vitro.
In human cohorts, we show that the 12 bp del associates with improved glucose metabolism (lower fasting plasma glucose, fasting plasma insulin, and HOMA IR). Cells transfected with the plasmid carrying the 12 bp del variant are characterized by increased GLUT2 and fatty acid translocase CD36 expression and more lipid droplets.
Our data suggest that genetic variation in human REPIN1 plays a role in glucose and lipid metabolism by differentially affecting the expression of REPIN1 target genes including glucose and fatty acid transporters.
复制起始因子 1（Repin1）是一种在肝脏和脂肪组织中高度表达的锌指蛋白。Repin1 位于大鼠体重和甘油三酯水平的数量性状位点（QTL）内，其在小鼠肝脏中的缺失导致胰岛素敏感性提高和体重降低。在这里，我们分析了 Repin1 内的遗传变异是否会影响葡萄糖和脂质代谢参数。
我们对 48 名非相关的白种人受试者进行了 REPIN1 测序。我们发现了一个 12 个碱基对的缺失（12bp del；rs3832490），随后在两个特征明确的队列（N=3013）中对其进行了基因分型，以测试其与代谢特征的关联。在体外的 HepG2 细胞中研究了该变体的功能后果。
在人类队列中，我们表明 12bp del 与改善的葡萄糖代谢（较低的空腹血糖、空腹胰岛素和 HOMA IR）相关。携带 12bp del 变体的质粒转染的细胞表现出 GLUT2 和脂肪酸转运蛋白 CD36 表达增加和更多的脂滴。
我们的数据表明，人类 REPIN1 中的遗传变异通过差异影响包括葡萄糖和脂肪酸转运蛋白在内的 Repin1 靶基因的表达，在葡萄糖和脂质代谢中发挥作用。
