Abstract
Liver X receptors (LXRs), LXRα and LXRβ, are members of the nuclear receptor superfamily
and regulate the expression of genes involved in the regulation of cholesterol and
fatty acid metabolism. Human plasma, unlike mouse plasma, contains cholesteryl ester
transfer protein (CETP), which plays an important role in reverse cholesterol transport
(RCT). LXRs induce CETP transcription via a direct repeat 4 element in the CETP promoter.
However, the specific roles of the individual LXR subtypes in CETP expression and
their consequences on plasma lipoprotein metabolism are still unclear. Here we showed
that synthetic LXR agonist enhanced plasma CETP activity and resulted in non-high
density lipoprotein (non-HDL) increase and HDL decrease in cynomolgus monkeys and
human CETP transgenic mice. To address the relative importance of the two LXR subtypes,
we investigated the effect of the suppression of both LXR subtypes on CETP expression
in HepG2 cells. CETP expression induced by the LXR agonist was significantly reduced
by LXRα knock-down, but not by LXRβ. Consistent with these data, CETP promoter activity
was enhanced by LXRα activation, whereas LXRβ activation had only a minor effect.
Furthermore, we investigated the effect of genetic deficiency of both LXR subtypes
in human CETP transgenic mice. LXRα deficiency abolished the augmentation of plasma
CETP activity and hepatic CETP expression induced by the synthetic LXR agonist, consequently
increasing HDL and decreasing non-HDL, whereas LXRβ deficiency did not affect CETP
activation. These findings indicate that LXRα has an essential role in the regulation
of CETP expression and maintaining RCT.
Keywords
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Article Info
Publication History
Published online: May 24, 2010
Accepted:
April 22,
2010
Received in revised form:
April 20,
2010
Received:
January 14,
2010
Identification
Copyright
© 2010 Elsevier Ireland Ltd. Published by Elsevier Inc. All rights reserved.
