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A targeted analysis reveals relevant shifts in the methylation and transcription of genes responsible for bile acid homeostasis and drug metabolism in non-alcoholic fatty liver disease
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Functional Pharmacology.
Duke Univ, Med Ctr, Dept Obstet & Gynecol, Durham, NC 27710 USA..
Univ Hosp Schleswig Holstein, Dept Internal Med 1, Kiel, Germany..
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2016 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 17, 462Article in journal (Refereed) Published
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Abstract [en]

Background: Non-alcoholic fatty liver disease (NAFLD) is associated with a high risk for liver cirrhosis and cancer. Recent studies demonstrate that NAFLD significantly impacts on the genome wide methylation and expression reporting top hit genes to be associated with e.g. diabetes mellitus. In a targeted analysis we specifically investigate to what extent NAFLD is associated with methylation and transcriptional changes in gene networks responsible for drug metabolism (DM) and bile acid (BA) homeostasis, which may trigger liver and system toxic events. Methods: We performed a systematic analysis of 73 genes responsible for BA homeostasis and DM based on liver derived methylation and expression data from three cohort studies including 103 NAFLD and 75 non-NAFLD patients. Using multiple linear regression models, we detected methylation differences in proximity to the transcriptional start site of these genes in two NAFLD cohorts and correlated the methylation of significantly changed CpG sites to transcriptional expression in a third cohort using robust multiple linear regression approaches. Results: We detected 64 genes involved in BA homeostasis and DM to be significantly differentially methylated. In 26 of these genes, methylation significantly correlated with RNA expression, detecting i.e. genes such as CYP27A1, OST alpha, and SLC27A5 (BA homeostasis), and SLCO2B1, SLC47A1, and several UGT and CYP genes (DM) to be NAFLD dependently modulated. Conclusions: NAFLD is associated with significant shifts in the methylation of key genes responsible for BA and DM that are associated with transcriptional modulations. These findings have implications for BA composition, BA regulated metabolic pathways and for drug safety and efficacy.

Place, publisher, year, edition, pages
2016. Vol. 17, 462
Keyword [en]
Liver, NAFLD, Methylation, Bile acid homeostasis, Drug metabolizing enzymes, Drug transporters, Correlation of methylation and transcriptional expression
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
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URN: urn:nbn:se:uu:diva-299722DOI: 10.1186/s12864-016-2814-zISI: 000378379600001PubMedID: 27301979OAI: oai:DiVA.org:uu-299722DiVA: diva2:950006
Funder
Swedish Society for Medical Research (SSMF)Swedish Research Council
Available from: 2016-07-26 Created: 2016-07-26 Last updated: 2017-11-28Bibliographically approved

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