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.
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.



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.



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, OSTɑ, and SLC27A5 (BA homeostasis), and SLCO2B1, SLC47A1, and several UGT and CYP genes (DM) to be NAFLD dependently modulated.



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.
Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, Uppsala, Sweden.
Helgi B
HB
Schiöth
Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, Uppsala, Sweden.
Adrian
A
Boström
Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA.
Susan K
SK
Murphy
Department of Internal Medicine I, University Hospital Schleswig-Holstein, Kiel, Germany.
Wiebke
W
Erhart
Medical Department I, University Hospital Dresden, Dresden, Germany.
Jochen
J
Hampe
Department of Medicine, Duke University Medical Center, Durham, NC, USA.|Department of Medicine, Durham Veterans Affairs Medical Center, Durham, NC, USA.
Cynthia
C
Moylan
Department of Neuroscience, Division of Functional Pharmacology, Uppsala University, Uppsala, Sweden. jessica.mwinyi@neuro.uu.se.
Jessica
J
Mwinyi
D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism*; D015897:Comorbidity; D018899:CpG Islands; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling; D006706:Homeostasis; D006801:Humans; D008658:Inactivation, Metabolic; D008103:Liver Cirrhosis / Q000209:etiology; D008297:Male; D053858:Metabolic Networks and Pathways; D008875:Middle Aged; D065626:Non-alcoholic Fatty Liver Disease / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D012307:Risk Factors; D014158:Transcription, Genetic
D001647:Bile Acids and Salts
Bile acid homeostasis; Correlation of methylation and transcriptional expression; Drug metabolizing enzymes; Drug transporters; Liver; Methylation; NAFLD