Liver-Restricted Repin1 Deficiency Improves Whole-Body Insulin Sensitivity, Alters Lipid Metabolism, and Causes Secondary Changes in Adipose Tissue in Mice

摘要

Replication initiator 1 (Repini) 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 con-genic and subcongenic rat strains. Here, we elucidated the role of Repini in lipid metabolism in vivo. We generated a liver-specific Repini knockout mouse (LRep1~(-/-)) and systematically characterized the consequences of Repini 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. Repini deficiency causes significant changes in potential downstream target molecules including Cd36, Pparγ, Glut2 protein, Akt phosphorylation, and lipoca-Iin2, 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 Iipocalin2 or chemerin. Our findings indicate that Repini plays a role in insulin sensitivity and lipid metabolism by regulating key genes of glucose and lipid metabolism.