Abstract
BackgroundEpigenetics can contribute to lipid disorders in obesity. The DNA methylation pattern can be the cause or consequence of high blood lipids. The aim of the study was to investigate the DNA methylation profile in peripheral leukocytes associated with elevated LDL-cholesterol level in overweight and obese individuals.MethodsTo identify the differentially methylated genes, genome-wide DNA methylation microarray analysis was performed in leukocytes of obese individuals with high LDL-cholesterol (LDL-CH, ≥ 3.4 mmol/L) versus control obese individuals with LDL-CH, < 3.4 mmol/L. Biochemical tests such as serum glucose, total cholesterol, HDL cholesterol, triglycerides, insulin, leptin, adiponectin, FGF19, FGF21, GIP and total plasma fatty acids content have been determined. Oral glucose and lipid tolerance tests were also performed. Human DNA Methylation Microarray (from Agilent Technologies) containing 27,627 probes for CpG islands was used for screening of DNA methylation status in 10 selected samples. Unpaired t-test and Mann–Whitney U-test were used for biochemical and anthropometric parameters statistics. For microarrays analysis, fold of change was calculated comparing hypercholesterolemic vs control group. The q-value threshold was calculated using moderated Student’s t-test followed by Benjamini–Hochberg multiple test correction FDR.ResultsIn this preliminary study we identified 190 lipid related CpG loci differentially methylated in hypercholesterolemic versus control individuals. Analysis of DNA methylation profiles revealed several loci engaged in plasma lipoprotein formation and metabolism, cholesterol efflux and reverse transport, triglycerides degradation and fatty acids transport and β-oxidation. Hypermethylation of CpG loci located in promoters of genes regulating cholesterol metabolism: PCSK9, LRP1, ABCG1, ANGPTL4, SREBF1 and NR1H2 in hypercholesterolemic patients has been found. Novel epigenetically regulated CpG sites include ABCG4, ANGPTL4, AP2A2, AP2M1, AP2S1, CLTC, FGF19, FGF1R, HDLBP, LIPA, LMF1, LRP5, LSR, NR1H2 and ZDHHC8 genes.ConclusionsOur results indicate that obese individuals with hypercholesterolemia present specific DNA methylation profile in genes related to lipids transport and metabolism. Detailed knowledge of epigenetic regulation of genes, important for lipid disorders in obesity, underlies the possibility to influence target genes by changing diet and lifestyle, as DNA methylation is reversible and depends on environmental factors. These findings give rise for further studies on factors that targets methylation of revealed genes.
Highlights
Epigenetics can contribute to lipid disorders in obesity
It is estimated that 70% of promoters in human genomes are rich in CpG sites indicating that DNA methylation serves as a crucial epigenetic modification (Blattler and Farnham 2013)
In leukocytes of patients with elevated serum Low Density Lipoprotein (LDL)-CH, we found hypomethylated promoters of the following genes involved in lipoprotein metabolism: LPL, LIPA, ZDHHC8, PRKACA, AMN and fibroblast growth factor 19 (FGF19); hypermethylated promoters of PCSK9, ABCG1, CLTC, AP2M1, AP2S1, LMF1, LSR, PRKACG, ANGPTL4, NR1H2, and PCSK5, and hypermethylated inside the following genes: LDL receptor (LDLR), HDLBP, AP2A2 and PCSK6 (Fig. 1 and Additional file 1: Table S1)
Summary
Epigenetics can contribute to lipid disorders in obesity. The DNA methylation pattern can be the cause or consequence of high blood lipids. Research over the last decade indicates that various environmental factors at different stages of life can changes to chromatin structure and function and change cellular phenotype and metabolism (Rosen et al 2018; Piening et al 2018; Jacobsen et al 2012; Stuart et al 2018; Roh et al 2018) Epigenetic modifications such as DNA methylation and multiple histone posttranslational modifications regulate gene transcription and adapt metabolism to environmental factors (Handel et al 2010; Keating and El-Osta 2015). The results of this work may contribute to a better understanding of the epigenetic mechanisms related to dyslipidemia
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