Biological Research Laboratories II, Daiichi Sankyo Co. Ltd., 1-2-58 Hiromachi, Shinagawa-ku, Tokyo 140-8710, Japan.
Atherosclerosis. 2010 Sep;212(1):139-45. doi: 10.1016/j.atherosclerosis.2010.04.025. Epub 2010 Apr 29.
Liver X receptors (LXRs), LXRalpha and LXRbeta, 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 LXRalpha knock-down, but not by LXRbeta. Consistent with these data, CETP promoter activity was enhanced by LXRalpha activation, whereas LXRbeta activation had only a minor effect. Furthermore, we investigated the effect of genetic deficiency of both LXR subtypes in human CETP transgenic mice. LXRalpha 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 LXRbeta deficiency did not affect CETP activation. These findings indicate that LXRalpha has an essential role in the regulation of CETP expression and maintaining RCT.
肝 X 受体（LXRs），LXRalpha 和 LXRbeta，是核受体超家族的成员，调节参与胆固醇和脂肪酸代谢调节的基因的表达。与小鼠血浆不同，人血浆中含有胆固醇酯转移蛋白（CETP），它在胆固醇逆转运（RCT）中发挥重要作用。LXRs 通过 CETP 启动子中的直接重复 4 元件诱导 CETP 转录。然而，个体 LXR 亚型在 CETP 表达中的特定作用及其对血浆脂蛋白代谢的影响尚不清楚。在这里，我们表明，合成 LXR 激动剂增强了血浆 CETP 活性，导致食蟹猴和人 CETP 转基因小鼠非高密度脂蛋白（non-HDL）增加和高密度脂蛋白（HDL）减少。为了解决两种 LXR 亚型的相对重要性问题，我们研究了抑制两种 LXR 亚型对 HepG2 细胞中 CETP 表达的影响。LXR 激动剂诱导的 CETP 表达被 LXRalpha 敲低显著降低，但 LXRbeta 敲低没有。与这些数据一致，LXRalpha 的激活增强了 CETP 启动子活性，而 LXRbeta 的激活仅有轻微影响。此外，我们研究了两种 LXR 亚型在人 CETP 转基因小鼠中的遗传缺失的影响。LXRalpha 缺陷消除了合成 LXR 激动剂诱导的血浆 CETP 活性和肝 CETP 表达的增强，从而增加了 HDL 并降低了非-HDL，而 LXRbeta 缺陷则不影响 CETP 的激活。这些发现表明，LXRalpha 在调节 CETP 表达和维持 RCT 方面具有重要作用。
