👤 Piotr Zabielski

Epigenetics 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. To 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. In 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. Our 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. Show less

Liver X receptors (LXRα and LXRβ) are ligand-activated transcription factors that regulate expression of genes involved in lipid and cholesterol metabolism. LXR expression has been identified in human and rodent cardiac tissue, however, its role in this tissue remains unclear. The aim of this study was to investigate effects of in vivo LXR activation on lipid metabolism in the rat myocardium under the conditions of low and high lipid intake. The experiments were performed on male Wistar rats fed for 5 weeks on either low fat diet (LFD) or high fat diet (HFD). Next, the animals were randomly divided into two groups receiving either LXR agonist - T0901317 (10mg/kg/d) or vehicle for the last week of the experiment. After anesthesia samples of the left ventricle and blood were taken. It was found that LXRβ is the dominant isoform in the rat myocardium and the expression of both LXR isoforms did not change after administration of T0901317. Agonist treatment induced hyperlipidemia in low fat fed rats and this effect was amplified in high fat fed rats. LXR agonist elevated content of myocardial triacylglycerols in animals fed on LFD and content of phospholipids in animals fed on HFD. Levels of the remaining examined lipid classes (nonesterified fatty acids, diacylglycerol, free cholesterol, cholesterol esters, ceramide) was decreased or unchaged after LXR activation. We conclude that administration of T0901317 does not lead to severe myocardial lipid accumulation in rats despite of its high plasma availability. Show less