Effects of lifestyle interventions on epigenetic signatures of liver fat: Central randomized controlled trial

Anat Yaskolka Meir, Maria Keller, Luise Müller, Stephan H. Bernhart, Gal Tsaban, Hila Zelicha, Ehud Rinott, Alon Kaplan, Yftach Gepner, Ilan Shelef, Dan Schwarzfuchs, Uta Ceglarek, Peter Stadler, Matthias Blüher, Michael Stumvoll, Peter Kovacs, Iris Shai

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


Background and Aims: In the CENTRAL trial context, we found diverse liver fat dynamics in response to different dietary interventions. Epigenetic mechanisms may contribute to the intraindividual variation. Moreover, genetic factors are involved in developing nonalcoholic fatty-liver disease (NAFLD), a disease reflected by an increase in intrahepatic fat (IHF). In this exploratory analysis, we primarily aimed to examine the effect of lifestyle interventions on DNA-methylation of NAFLD related genes associated with IHF. Methods: For 120 participants from the CENTRAL trial, an 18-month regimen of either low-fat (LF) or Mediterranean-low carbohydrate (MED/LC) diets, with or without physical activity (PA+/PA−), was instructed. Magnetic resonance imaging was used to measure IHF%, which was analysed for association with CpG specific DNA-methylation levels of 41 selected candidate genes. Single-nucleotide polymorphisms known to be associated with NAFLD within the studied genes were genotyped by TaqMan assays. Results: At baseline, participants (92% men; body mass index = 30.2 kg/m2) had mean IHF of 10.7% (59% NAFLD). Baseline-IHF% was inversely correlated with DNA-methylation at individual CpGs within AC074286.1, CRACR2A, A2MP1, FARP1 (P <.05 for all multivariate models). FARP1 rs9584805 showed association with IHF, with the prevalence of NAFLD and baseline methylation level of the CpG site (cg00071727) associated with IHF%. Following 18-month lifestyle intervention, differential DNA-methylation patterns were observed between diets at cg14335324 annotated to A2MP1 (P =.04, LF vs. MED/LC), and differential DNA-methylation between PA groups within AC074286.1, CRACR2A, and FARP1 CpGs (P <.05 for all, PA−vs. PA+). Conclusions: This study suggests epigenetic markers for IHF and potential epigenetic remodeling after long-term lifestyle interventions.

Original languageEnglish
Pages (from-to)2101-2111
Number of pages11
JournalLiver International
Issue number9
StatePublished - 1 Sep 2021


  • Diet
  • DNA-methylation
  • genetic variation
  • nonalcoholic fatty liver disease
  • physical activity

ASJC Scopus subject areas

  • Hepatology


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