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 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 1alpha (HNF1alpha) 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.
Richert
Lysiane
L
Laboratoire de Biologie Cellulaire, UFR SMP, 4, place Saint-Jacques, 25030 Besançon, France. lysiane.richert@univ-fcomte.fr
Lamboley
Christelle
C
Viollon-Abadie
Catherine
C
Grass
Peter
P
Hartmann
Nicole
N
Laurent
Stephane
S
Heyd
Bruno
B
Mantion
Georges
G
Chibout
Salah-Dine
SD
Staedtler
Frank
F
D000368:Aged; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001692:Biological Transport / Q000187:drug effects; D002462:Cell Membrane / Q000378:metabolism; D002995:Clofibric Acid / Q000378:metabolism / Q000494:pharmacology*; D015536:Down-Regulation; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D022781:Hepatocytes / Q000378:metabolism*; D006801:Humans; D000960:Hypolipidemic Agents / Q000378:metabolism / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D013045:Species Specificity; D015854:Up-Regulation
D005227:Fatty Acids; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D002995:Clofibric Acid