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Yaskolka Meir, A.* ; Keller, M. ; Müller, L.* ; Bernhart, S.H.* ; Tsaban, G.* ; Zelicha, H.* ; Rinott, E.* ; Kaplan, A.* ; Gepner, Y.* ; Shelef, I.* ; Schwarzfuchs, D.* ; Ceglarek, U.* ; Blüher, M. ; Stumvoll, M. ; Kovacs, P.* ; Shai, I.*

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

Liver Int. 41, 2101-2111 (2021)

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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 non-alcoholic 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 NAFLD's DNA-methylation-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 analyzed 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=30.2kg/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<0.05 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=0.04, LF vs. MED/LC), and differential DNA-methylation between PA groups within AC074286.1, CRACR2A, and FARP1 CpGs (p<0.05 for all, PA- vs. PA+). CONCLUSIONS: This study suggests epigenetic markers for IHF and potential epigenetic remodeling after long-term lifestyle interventions.

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