DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery.
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.
Department of General and Thoracic Surgery, Christian-Albrechts-University Kiel/University Hospital Schleswig-Holstein, Germany.
Markus
M
Ahrens
Ole
O
Ammerpohl
Witigo
W
von Schönfels
Julia
J
Kolarova
Susanne
S
Bens
Timo
T
Itzel
Andreas
A
Teufel
Alexander
A
Herrmann
Mario
M
Brosch
Holger
H
Hinrichsen
Wiebke
W
Erhart
Jan
J
Egberts
Bence
B
Sipos
Stefan
S
Schreiber
Robert
R
Häsler
Felix
F
Stickel
Thomas
T
Becker
Michael
M
Krawczak
Christoph
C
Röcken
Reiner
R
Siebert
Clemens
C
Schafmayer
Jochen
J
Hampe
D000328:Adult; D000368:Aged; D050110:Bariatric Surgery / Q000009:adverse effects*; D019175:DNA Methylation / Q000235:genetics*; D005234:Fatty Liver / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease; D009767:Obesity, Morbid / Q000235:genetics / Q000378:metabolism / Q000601:surgery*; D015398:Signal Transduction / Q000235:genetics
D007328:Insulin