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

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 expresse...

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Bibliographic Details
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
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Summary: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.
ISSN:0041-008X
1096-0333
DOI:10.1016/S0041-008X(03)00231-X