Diabetologie und Stoffwechsel 2016; 11 - P164
DOI: 10.1055/s-0036-1580911

Differences on hepatic Igfbp2 methylation and expression occur before the onset of fatty liver disease

A Kammel 1, 2, S Saussenthaler 1, 2, M Jähnert 1, 2, W Jonas 1, 2, HG Joost 1, 2, A Schürmann 1, 2, RW Schwenk 1, 2
  • 1German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Department of Experimental Diabetology, Potsdam, Germany
  • 2German Center for Diabetes Research, München-Neuherberg, Germany

Background: NAFLD patients exhibit decreased hepatic Insulin-like growth factor binding protein-2 (IGFBP2) expression associated with decreased DNA methylation1. Transcriptome analysis of livers from adiposity-susceptible (responder) C57BL/6J mice showed also decreased expression levels of hepatic Igfbp2 compared to adiposity-resistant (non-responder) mice. The aim of this study was to test if hepatic DNA methylation and Igfbp2 expression is altered before onset of hepatosteatosis.

Methods: Male C57BL/6J mice on high-fat diet were grouped into responder or non-responder using previously established prediction criteria (body weight development after weaning). Determination of hepatic expression of Igfbp2 by qPCR and DNA methylation by pyrosequencing were performed at week 6 and 20. Determination of DNA methylation on promoter activity was studied by luciferase reporter assay.

Results: Responder mice exhibited decreased Igfbp2 expression by 40% at week 6 and week 20. Accordingly, IGFBP-2 plasma levels were reduced by 17.4% at week 6. At this early time point, mice did not differ in liver fat concentration. However, in week 20 responder mice revealed elevated hepatic triglyceride concentrations by 40%. Decreased expression and plasma IGFBP-2 levels were associated with increased DNA methylation (week 6: +5.29%; week 20: +5.12%) of CpG2605 of Igfbp2, which is conserved in the human IGFBP2. Selective in vitro methylation of CpG2605 led to reduction of luciferase activity by 84.8%.

Conclusion: Differences in DNA methylation and expression of Igfbp2 gene occur before onset of liver fat accumulation and therefore may function as prediction marker for fatty liver diseases.

Reference: 1Ahrens et al. Cell Metab. 2013

Funding: BMBF: DZD.