Inferring statin-induced gene regulatory relationships in primary human hepatocytes

Bioinformatics. 2011 Sep 15;27(18):2473-7. doi: 10.1093/bioinformatics/btr416. Epub 2011 Jul 14.


Motivation: Statins are the most widely used cholesterol-lowering drugs. The primary target of statins is HMG-CoA reductase, a key enzyme in cholesterol synthesis. However, statins elicit pleitropic responses including beneficial as well as adverse effects in the liver or other organs. Today, the regulatory mechanisms that cause these pleiotropic effects are not sufficiently understood.

Results: In this work, genome-wide RNA expression changes in primary human hepatocytes of six individuals were measured at up to six time points upon atorvastatin treatment. A computational analysis workflow was applied to reconstruct regulatory mechanisms based on these drug-response data and available knowledge about transcription factor (TF) binding specificities and protein-drug interactions. Several previously unknown TFs were predicted to be involved in atorvastatin-responsive gene expression. The novel relationships of nuclear receptors NR2C2 and PPARA on CYP3A4 were successfully validated in wet-lab experiments.

Availability: Microarray data are available at the Gene Expression Omnibus (GEO) database at, under accession number GSE29868.


Supplementary information: Supplementary data are available at Bioinformatics online.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticholesteremic Agents / pharmacology
  • Atorvastatin
  • Cytochrome P-450 CYP3A / metabolism
  • Drug Interactions
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Genes, Regulator / drug effects*
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Heptanoic Acids / pharmacology*
  • Humans
  • Hydroxymethylglutaryl CoA Reductases / metabolism
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology*
  • Liver / drug effects
  • Liver / metabolism
  • Molecular Sequence Data
  • Protein Binding
  • Pyrroles / pharmacology*
  • RNA / metabolism
  • Transcription Factors / metabolism


  • Anticholesteremic Agents
  • Heptanoic Acids
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Pyrroles
  • Transcription Factors
  • RNA
  • Atorvastatin
  • Hydroxymethylglutaryl CoA Reductases
  • Cytochrome P-450 CYP3A

Associated data

  • GEO/GSE29868