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J Biol Chem, Vol. 273, Issue 40, 25713-25720, October 2, 1998
and Rev-erb Mediate the Species-specific Regulation of
Apolipoprotein A-I Expression by Fibrates
,,,,
From the Fibrates are widely used hypolipidemic drugs
which activate the nuclear peroxisome proliferator-activated receptor
(PPAR) U.325 INSERM, Département
d'Athérosclérose, Institut Pasteur, and the Faculté
de Pharmacie, Université de Lille II, Lille, France and
¶ Endocrin'os group, CNRS UMR319, Institut de Biologie de Lille,
Lille, France
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-erb, which binds to a negative response element adjacent to the TATA box of the
rat apoA-I promoter. In rats fibrates increase liver Rev-erb 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-erb of rat apoA-I and activation by
PPAR of human apoA-I. Finally, Rev-erb is identified as a novel
fibrate target gene, suggesting a role for this nuclear receptor in
lipid and lipoprotein metabolism.
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