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Genetics and Epigenetics

Metabolic effects of genetic variation in the human REPIN1 gene

International Journal of Obesity volume 43, pages 821–831 (2019)Cite this article

Subjects

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.

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Acknowledgements

We thank all those who participated in the studies. We would like to acknowledge excellent technical assistance by Ines Müller, Beate Gutsmann, Manuela Quandt, and Viola Döbel. This work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) (SFB 1052 “Obesity mechanisms’, projects B01, B03, B04, C01), from the Deutsche Diabetes Stiftung (DDS- Funktionelle Charakterisierung Adipositas- und Typ 2 Diabetes-assoziierter Varianten im Repin1-Gen), Deutsche Diabetes Gesellschaft (DDG 934300-003) and Deutsches Zentrum für Diabetesforschung (DZD 8200601). IFB Adiposity Diseases is supported by the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 (AD2-060E, AD2-06E95, AD2-06E99). The authors declare no conflict of interest.

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Author notes

  1. These authors contributed equally: Jacqueline Krüger, Claudia Berger.

Authors and Affiliations

  1. Leipzig University Medical Center, IFB Adiposity Diseases, University of Leipzig, 04103, Leipzig, Germany

    Jacqueline Krüger, Claudia Berger, Kerstin Weidle, Dorit Schleinitz, Peter Kovacs & Nora Klöting

  2. German Diabetes Center Leipzig, University of Leipzig, 04103, Leipzig, Germany

    Claudia Berger

  3. Department of Medicine, University of Leipzig, 04103, Leipzig, Germany

    Anke Tönjes, Michael Stumvoll & Matthias Blüher

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  1. Jacqueline Krüger
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Correspondence to Peter Kovacs or Nora Klöting.

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Krüger, J., Berger, C., Weidle, K. et al. Metabolic effects of genetic variation in the human REPIN1 gene. Int J Obes 43, 821–831 (2019). https://doi.org/10.1038/s41366-018-0123-0

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