Effects of clofibric acid on mRNA expression profiles in primary cultures of rat, mouse and human hepatocytes

• Published in: Toxicology and applied pharmacology 2003-09, Vol.191 (2), p.130-146
• Main Authors: Richert, Lysiane, Lamboley, Christelle, Viollon-Abadie, Catherine, Grass, Peter, Hartmann, Nicole, Laurent, Stephane, Heyd, Bruno, Mantion, Georges, Chibout, Salah-Dine, Staedtler, Frank
• Format: Article
• Language: English
• Subjects: Aged; Animals; Apoptosis - drug effects; Biological and medical sciences; Biological Transport - drug effects; Cell Membrane - metabolism; Clofibric acid; Clofibric Acid - metabolism; Clofibric Acid - pharmacology; Down-Regulation; Drug toxicity and drugs side effects treatment; Fatty Acids - metabolism; Female; Gene expression profiling; Gene Expression Regulation - drug effects; Hepatocytes - metabolism; Human; Humans; Hypolipidemic Agents - metabolism; Hypolipidemic Agents - pharmacology; In Vitro Techniques; Male; Medical sciences; Mice; Middle Aged; Mouse; Oligonucleotide Array Sequence Analysis; Pharmaco/Toxicogenomics; Pharmacology. Drug treatments; Primary hepatocyte cultures; Rat; Rats; RNA, Messenger - biosynthesis; RNA, Messenger - genetics; Species Specificity; Toxicity: digestive system; Up-Regulation
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/S0041-008X(03)00231-X

The mRNA expression profile in control and clofibric acid (CLO)-treated mouse, rat, and human hepatocytes was analyzed using species-specific oligonucleotide DNA microarrays (Affymetrix). A statistical empirical Bayes procedure was applied in order to select the significantly differentially expressed genes. Treatment with the peroxisome proliferator CLO induced up-regulation of genes involved in peroxisome proliferation and in cell proliferation as well as down-regulation of genes involved in apoptosis in hepatocytes of rodent but not of human origin. CLO treatment induced up-regulation of microsomal cytochrome P450 4a genes in rodent hepatocytes and in two of six human hepatocyte cultures. In addition, genes encoding phenobarbital-inducible cytochrome P450s were also up-regulated by CLO in rodent and human hepatocyte cultures. Up-regulation of phenobarbital-inducible UDP-glucuronosyl-transferase genes by CLO was observed in both rat and human but not in mouse hepatocytes. CLO treatment induced up-regulation of l-fatty acid binding protein ( l-FABP) gene in hepatocytes of both rodent and human origin. However, while genes of the cytosolic, microsomal, and mitochondrial pathways involved in fatty acid transport and metabolism were up-regulated by CLO in both rodent and human hepatocyte cultures, genes of the peroxisomal pathway of lipid metabolism were up-regulated in rodents only. An up-regulation of hepatocyte nuclear factor 1α (HNF1α) by CLO was observed only in human hepatocyte cultures, suggesting that this trans-activating factor may play a key role in the regulation of fatty acid metabolism in human liver as well as in the nonresponsiveness of human liver to CLO-induced regulation of cell proliferation and apoptosis.