Jacqueline Krüger1, Claudia Berger1,2, Kerstin Weidle1, Dorit Schleinitz1, Anke Tönjes3, Michael Stumvoll3, Matthias Blüher3, Peter Kovacs4, Nora Klöting5. 1. Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, 04103, Leipzig, Germany. 2. German Diabetes Center Leipzig, University of Leipzig, 04103, Leipzig, Germany. 3. Department of Medicine, University of Leipzig, 04103, Leipzig, Germany. 4. Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, 04103, Leipzig, Germany. peter.kovacs@medizin.uni-leipzig.de. 5. Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, 04103, Leipzig, Germany. nora.kloeting@medizin.uni-leipzig.de.
Abstract
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.
BACKGROUND: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. METHODS: 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. RESULTS: 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. CONCLUSION: Our data suggest that genetic variation in humanREPIN1 plays a role in glucose and lipid metabolism by differentially affecting the expression of REPIN1 target genes including glucose and fatty acid transporters.