The nuclear receptors peroxisome proliferator-activated receptor alpha and Rev-erbalpha mediate the species-specific regulation of apolipoprotein A-I expression by fibrates.
Fibrates are widely used hypolipidemic drugs which activate the nuclear peroxisome proliferator-activated receptor (PPAR) alpha and thereby alter the transcription of genes controlling lipoprotein metabolism. Fibrates influence plasma high density lipoprotein and its major protein, apolipoprotein (apo) A-I, in an opposite manner in man (increase) versus rodents (decrease). In the present study we studied the molecular mechanisms of this species-specific regulation of apoA-I expression by fibrates. In primary rat and human hepatocytes fenofibric acid, respectively, decreased and increased apoA-I mRNA levels. The absence of induction of rat apoA-I gene expression by fibrates is due to 3 nucleotide differences between the rat and the human apoA-I promoter A site, rendering a positive PPAR-response element in the human apoA-I promoter nonfunctional in rats. In contrast, rat, but not human, apoA-I transcription is repressed by the nuclear receptor Rev-erbalpha, which binds to a negative response element adjacent to the TATA box of the rat apoA-I promoter. In rats fibrates increase liver Rev-erbalpha mRNA levels >10-fold. In conclusion, the opposite regulation of rat and human apoA-I gene expression by fibrates is linked to differences in cis-elements in their respective promoters leading to repression by Rev-erbalpha of rat apoA-I and activation by PPARalpha of human apoA-I. Finally, Rev-erbalpha is identified as a novel fibrate target gene, suggesting a role for this nuclear receptor in lipid and lipoprotein metabolism.
Vu-Dac
N
N
U.325 INSERM, Département d'Athérosclérose, Institut Pasteur, and the Faculté de Pharmacie, Université de Lille II, Lille, France.
Chopin-Delannoy
S
S
Gervois
P
P
Bonnelye
E
E
Martin
G
G
Fruchart
J C
JC
Laudet
V
V
Staels
B
B
D000818:Animals; D016632:Apolipoprotein A-I / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D011345:Fenofibrate / Q000031:analogs & derivatives / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000235:genetics*; D000960:Hypolipidemic Agents / Q000494:pharmacology; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000502:physiology; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology; D014407:Tumor Cells, Cultured
D016632:Apolipoprotein A-I; D004268:DNA-Binding Proteins; D000960:Hypolipidemic Agents; D008074:Lipoproteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; C006012:fenofibric acid; D011345:Fenofibrate