Kern Matthias, Kosacka Joanna, Hesselbarth Nico, Brückner Julia, Heiker John T, Flehmig Gesine, Klöting Ingrid, Kovacs Peter, Matz-Soja Madlen, Gebhardt Rolf, Krohn Knut, Sales Susanne, Abshagen Kerstin, Shevchenko Andrej, Stumvoll Michael, Blüher Matthias, Klöting Nora
Department of Medicine, University of Leipzig, Leipzig, Germany.
IFB AdiposityDiseases, University of Leipzig, Leipzig, Germany.
Diabetes. 2014 Oct;63(10):3295-309. doi: 10.2337/db13-0933. Epub 2014 Apr 23.
Replication initiator 1 (Repin1) is a zinc finger protein highly expressed in liver and adipose tissue and maps within a quantitative trait locus (QTL) for body weight and triglyceride (TG) levels in the rat. The QTL has further been supported as a susceptibility locus for dyslipidemia and related metabolic disorders in congenic and subcongenic rat strains. Here, we elucidated the role of Repin1 in lipid metabolism in vivo. We generated a liver-specific Repin1 knockout mouse (LRep1(-/-)) and systematically characterized the consequences of Repin1 deficiency in the liver on body weight, glucose and lipid metabolism, liver lipid patterns, and protein/mRNA expression. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved whole-body insulin sensitivity in LRep1(-/-) mice, which may be due to significantly lower TG content in the liver. Repin1 deficiency causes significant changes in potential downstream target molecules including Cd36, Pparγ, Glut2 protein, Akt phosphorylation, and lipocalin2, Vamp4, and Snap23 mRNA expression. Mice with hepatic deletion of Repin1 display secondary changes in adipose tissue function, which may be mediated by altered hepatic expression of lipocalin2 or chemerin. Our findings indicate that Repin1 plays a role in insulin sensitivity and lipid metabolism by regulating key genes of glucose and lipid metabolism.
复制起始因子1（Repin1）是一种锌指蛋白，在肝脏和脂肪组织中高度表达，其基因定位于大鼠体重和甘油三酯（TG）水平的数量性状基因座（QTL）内。该QTL在近交系和亚近交系大鼠中作为血脂异常及相关代谢紊乱的易感基因座得到了进一步证实。在此，我们阐明了Repin1在体内脂质代谢中的作用。我们构建了肝脏特异性Repin1基因敲除小鼠（LRep1(-/-)），并系统地研究了肝脏中Repin1缺乏对体重、葡萄糖和脂质代谢、肝脏脂质谱以及蛋白质/ mRNA表达的影响。高胰岛素-正葡萄糖钳夹试验显示，LRep1(-/-)小鼠的全身胰岛素敏感性显著改善，这可能是由于肝脏中TG含量显著降低所致。Repin1缺乏导致包括Cd36、Pparγ、Glut2蛋白、Akt磷酸化以及lipocalin2、Vamp4和Snap23 mRNA表达等潜在下游靶分子发生显著变化。肝脏中Repin1缺失的小鼠脂肪组织功能出现继发性改变，这可能由lipocalin2或chemerin肝脏表达改变介导。我们的研究结果表明，Repin1通过调节葡萄糖和脂质代谢的关键基因在胰岛素敏感性和脂质代谢中发挥作用。
