The Nuclear Receptors Peroxisome Proliferator-activated Receptor α and Rev-erbα Mediate the Species-specific Regulation of Apolipoprotein A-I Expression by Fibrates

Abstract

Fibrates are widely used hypolipidemic drugs which activate the nuclear peroxisome proliferator-activated receptor (PPAR) ␣ 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.

Role of Esrrg in the fibrate-mediated regulation of lipid metabolism genes in human ApoA-I transgenic mice

“…20 The different responses of the human and mouse Apoa1 genes to the fenofibrate treatment was attributed to differences between the human and rodent Apoa1 promoter. 41 This study shows that the in vivo regulation of the human apoA-I gene in mice when it contains its proximal and distal regulatory sequences resembles the regulation of the mouse Apoa1 gene described previously. 20 The observed differences between the present and the previous studies, 20,23,24 can be explained based on the mechanism of transcriptional regulation of the human APOA-I gene that emerged from in vitro and in vivo studies.…”

Effects of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ agonists on glucose and lipid metabolism in patients with type 2 diabetes mellitus

“…In rats, fibrate treatment lowers hepatic, but not intestinal, apoliprotein (apo) A-I levels, due to a decreased transcription rate of the apoA-I gene in liver. In contrast, the transcription rate of the human apoA-I gene is induced by PPAR-α via its interaction with a positive PPAR response element located in the human apoA-I gene promoter liver-specific enhancer [45]. At present, there is no clear explanation for the markedly discrepant results obtained in rodents vs humans.…”

PPAR-α effects on the heart and other vascular tissues

“…Synthesis of apo A-I and apo A-II, the two major proteins of HDL, by the liver and intestine is the first step in HDL particle formation. PPAR-␣ activation by fibrates activates human apo A-I and apo A-II genes in the liver, leading to increased synthesis of these proteins (95)(96)(97)(98). A recent study (36) using rabbits expressing the human apo A-I transgene along with its PPRE showed an increase in human apo A-I mRNA and mass in response to fenofibrate treatment in the absence of any peroxisome-proliferative effect of the fibrate.…”