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Biochim Biophys Acta Mol Cell Biol Lipids. 2017 Mar;1862(3):314-323. doi: 10.1016/j.bbalip.2016.12.005. Epub 2016 Dec 18.

NAFLD is associated with methylation shifts with relevance for the expression of genes involved in lipoprotein particle composition.

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Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden. Electronic address:
Department of Neuroscience, Functional Pharmacology, Uppsala University, Uppsala, Sweden.
Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy.
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
Department of General Surgery and Thoracic Surgery, University Hospital Schleswig-Holstein, Kiel, Germany.
Medical Department I, University Hospital Dresden, Dresden, Germany.
Department of Medicine, Duke University Medical Center, Durham, NC, USA; Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC, USA.


Non-alcoholic fatty liver disease (NAFLD) is characterized by the accumulation of triglycerides, cholesterol and toxic free fatty acids and is related to low vitamin D levels. In an analysis of specific gene sets we elucidate to what extent NAFLD associates to epigenetic and related transcriptional changes in gene networks regulating lipid, energy and vitamin D balance. Two gene clusters responsible for lipid homeostasis (74 genes) and vitamin D and energy balance (31 genes) were investigated with regard to average epigenetic shifts within the first 1500bp next to the transcriptional start site. Three cohorts from two published genome wide driven studies that used a microarray approach were investigated including altogether 103 NAFLD and 75 liver healthy subjects. In the first two steps associations between NAFLD abundance, strength of fibrosis and methylation were investigated in two cohorts by multiple linear regression analyses, correcting for important clinical and demographic parameters. Methylation associated strength of transcription in genes showing significant NAFLD related methylation changes were studied in a third step using a third cohort and applying Pearson's correlation and robust linear regression analyses. 41 genes in gene cluster 1 and 14 genes in cluster 2 were significantly differentially methylated in dependency of NAFLD and hepatic fibrosis. We detect new genes significantly changed in methylation, including APO family members (lipid transport), NPC1L1, STARD (cholesterol transport) and GRHL (energy homeostasis). Our results allow novel insights into the hepatic epigenetic regulation of genes important for lipid and vitamin D balance in NAFLD.


Lipid and lipoprotein metabolism; Liver; Methylation; NAFLD; NASH; Transcription

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