title: Chenodeoxycholic acid significantly impacts the expression of miRNAs and genes involved in lipid, bile acid and drug metabolism in human hepatocytes.
abstract: OBJECTIVE
  Bile acids (BAs) are important gut signaling hormones, influencing lipid, glucose, and energy homeostasis. The exact mechanisms behind these effects are not yet fully understood. Lately, they have come to the fore as putative therapeutics in metabolic diseases, such as e.g. nonalcoholic fatty liver disease (NAFLD). We elucidate to what extent BAs impacts on the mRNAome and microRNAome in hepatocytes to gather novel insights into the mechanisms behind metabolic and toxicologic effects of bile acids.
  
  
  METHODS
  Five batches of primary human hepatocytes were treated with 50μmol/l chenodeoxycholic acid (CDCA) for 24 or 48h. Total RNA was extracted, size fractionated and subjected to Next Generation Sequencing to generate mRNA and miRNA profiles.
  
  
  RESULTS
  Expression of 738 genes and 52 miRNAs were CDCA dependently decreased, whereas 1566 genes and 29 miRNAs were significantly increased in hepatocytes. Distinct gene clusters controlling BA and lipid homeostasis (FGF(R), APO and FABP family members, HMGCS2) and drug metabolism (CYP, UGT and SULT family members) were significantly modulated by CDCA. Importantly, CDCA affected distinct microRNAs, including miR-34a, -505, -885, -1260 and -552 that systematically correlated in expression with gene clusters responsible for bile acid, lipid and drug homeostasis incorporating genes, such as e.g. SLCO1B1, SLC22A7, FGF19, CYP2E1, CYP1A2, APO family members and FOXO3.
  
  
  CONCLUSIONS
  Bile acids significantly modulate metabolic and drug associated gene networks that are connected to distinct shifts in the microRNAome These findings give novel insights on how BA enfold metabolic and system toxic effects.
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland.
authors.forename: Regina
authors.initials: R
authors.lastname: Krattinger
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Adrian
authors.initials: A
authors.lastname: Boström
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany.
authors.forename: Serene M L
authors.initials: SML
authors.lastname: Lee
authors.affiliation: Department of General, Visceral, Transplantation, Vascular and Thoracic Surgery, Hospital of the University of Munich, Munich, Germany.
authors.forename: Wolfgang E
authors.initials: WE
authors.lastname: Thasler
authors.affiliation: Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Helgi B
authors.initials: HB
authors.lastname: Schiöth
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland. Electronic address: gerd.kullak@usz.ch.
authors.forename: Gerd A
authors.initials: GA
authors.lastname: Kullak-Ublick
authors.affiliation: Department of Clinical Pharmacology and Toxicology, University Hospital Zurich, University of Zurich, Switzerland; Division of Pharmacology, Department of Neuroscience, Uppsala University, Uppsala, Sweden.
authors.forename: Jessica
authors.initials: J
authors.lastname: Mwinyi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects / Q000235:genetics; D002635:Chenodeoxycholic Acid / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000235:genetics; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014801:Vitamin A / Q000378:metabolism
chemical_list: D001647:Bile Acids and Salts; D035683:MicroRNAs; D004364:Pharmaceutical Preparations; D012333:RNA, Messenger; D002635:Chenodeoxycholic Acid; D014801:Vitamin A; D004958:Estradiol
keywords: Bile acids; Chenodeoxycholic acid; Primary human hepatocytes; mRNA profiling; microRNA profiling; microRNA-34a