title: The human primary hepatocyte transcriptome reveals novel insights into atorvastatin and rosuvastatin action.
abstract: OBJECTIVE
  With particular emphasis on interactions between cholesterol homeostasis and drug metabolism we investigate the transcriptome of human primary hepatocytes treated by two commonly prescribed cholesterol lowering drugs atorvastatin and rosuvastatin and by rifampicin that serves as an outgroup as well as a model substance for induction of nuclear pregnane X receptor.
  
  
  METHODS
  Hepatocytes from human donors have been treated with rosuvastatin, atorvastatin, and rifampicin for 12, 24, and 48 h. Expression profiling with cholesterol and drug metabolism enriched low density Steroltalk cDNA and whole genome Affymetrix HG-U133 Plus 2.0 arrays has been applied. Differential expression (DE) of genes and gene set enrichment analysis of KEGG pathways were performed. Lists of differentially expressed genes and gene sets were cross-compared. Selected genes were confirmed by quantitative real-time PCR.
  
  
  RESULTS
  Statins lead to: (a) upregulation of cholesterol-related genes indicating an increased LDL uptake and storage of esterified cholesterol, elevated bile acid/drug export and lower capacity to form HDL; (b) perturbation of genes in glucose and fatty acid homeostasis, influencing acetyl-CoA pools, promoting gluconeogenesis and glucose export; (c) elevated expression of ADIPOR2 suggesting increased sensitivity to adiponectin; (d) perturbations in genes of lipoprotein particle formation, differently for each statin; (e) perturbed expression of many metabolic genes that are directly controlled by nuclear receptors constitutive androstan and/or pregnane X.
  
  
  CONCLUSIONS
  These data provide a novel global insight into hepatic effects of statins, offering biochemical explanations for higher blood glucose in statin-treated patients, and for drug-induced secondary fatty liver disease.
authors.affiliation: Center for Functional Genomics and Bio-Chips, Institute of Biochemistry, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia.
authors.forename: Mateja
authors.initials: M
authors.lastname: Hafner
authors.forename: Peter
authors.initials: P
authors.lastname: Juvan
authors.forename: Tadeja
authors.initials: T
authors.lastname: Rezen
authors.forename: Katalin
authors.initials: K
authors.lastname: Monostory
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Pascussi
authors.forename: Damjana
authors.initials: D
authors.lastname: Rozman
mesh_terms: D000069059:Atorvastatin; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005464:Fluorobenzenes / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D053858:Metabolic Networks and Pathways / Q000187:drug effects / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D000077297:Pregnane X Receptor; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D000068718:Rosuvastatin Calcium; D013449:Sulfonamides / Q000494:pharmacology*; D059467:Transcriptome
chemical_list: D000090702:Constitutive Androstane Receptor; D005464:Fluorobenzenes; D006538:Heptanoic Acids; D026901:Membrane Transport Proteins; D000077297:Pregnane X Receptor; D011743:Pyrimidines; D011758:Pyrroles; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D002784:Cholesterol; D000069059:Atorvastatin