LXRa regulates human CETP expression in vitro and in transgenic mice

Liver X receptors (LXRs), LXRa and LXRb, 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 imp...

Full description

Saved in:
Bibliographic Details
Published in:Atherosclerosis 2010-09, Vol.212 (1), p.139-145
Main Authors: Honzumi, Shoko, Shima, Akiko, Hiroshima, Ayano, Koieyama, Tadashi, Ubukata, Naoko, Terasaka, Naoki
Format: Article
Language:English
Subjects:
Arteriosclerosis
Cynomolgus
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Liver X receptors (LXRs), LXRa and LXRb, 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 LXRa knock-down, but not by LXRb. Consistent with these data, CETP promoter activity was enhanced by LXRa activation, whereas LXRb activation had only a minor effect. Furthermore, we investigated the effect of genetic deficiency of both LXR subtypes in human CETP transgenic mice. LXRa 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 LXRb deficiency did not affect CETP activation. These findings indicate that LXRa has an essential role in the regulation of CETP expression and maintaining RCT.
ISSN:0021-9150
DOI:10.1016/j.atherosclerosis.2010.04.025