DNA Methylation Analysis in Nonalcoholic Fatty Liver Disease Suggests Distinct Disease-Specific and Remodeling Signatures after Bariatric Surgery

• DOI: 10.1016/j.cmet.2013.07.004
• Publication Date: 2013-08-06T23:47:44Z
• Authors: Markus Ahrens; Ole Ammerpohl; Witigo von Schönfels; Julia Kolarova; Susanne Bens; Timo Itzel; Andreas Teufel; Alexander Herrmann; Mario Brosch; Holger Hinrichsen; Wiebke Erhart; Jan Egberts; Bence Sipos; Stefan Schreiber; Robert Häsler; Felix Stickel; Thomas Becker; Michael Krawczak; Christoph Röcken; Reiner Siebert; Clemens Schafmayer; Jochen Hampe
• Keywords: FGF21; CpG site

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries. Liver samples from morbidly obese patients (n = 45) with all stages of NAFLD and controls (n = 18) were analyzed by array-based DNA methylation and mRNA expression profiling. NAFLD-specific expression and methylation differences were seen for nine genes coding for key enzymes in intermediate metabolism (including PC, ACLY, and PLCG1) and insulin/insulin-like signaling (including IGF1, IGFBP2, and PRKCE) and replicated by bisulfite pyrosequening (independent n = 39). Transcription factor binding sites at NAFLD-specific CpG sites were >1,000-fold enriched for ZNF274, PGC1A, and SREBP2. Intraindividual comparison of liver biopsies before and after bariatric surgery showed NAFLD-associated methylation changes to be partially reversible. Postbariatric and NAFLD-specific methylation signatures were clearly distinct both in gene ontology and transcription factor binding site analyses, with >400-fold enrichment of NRF1, HSF1, and ESRRA sites. Our findings provide an example of treatment-induced epigenetic organ remodeling in humans.