Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta.
Regulation of ATP-binding cassette sterol transporters ABCG5 and ABCG8 by the liver X receptors alpha and beta.
复制标题
DOI：
--
复制
发表时间：
2002
期刊：
影响因子：
--
通讯作者：
J. Repa;K. Berge;Chris Pomajzl;J. Richardson;H. Hobbs;D. Mangelsdorf
中科院分区：
文献类型：
--
作者：
J. Repa;K. Berge;Chris Pomajzl;J. Richardson;H. Hobbs;D. Mangelsdorf
最近发现，三磷酸腺苷结合盒(ABC)转运体ABCG5和ABCG8的突变可导致常染色体隐性遗传性谷甾醇血症。在这里，我们证明ABCG5和ABCG8基因是氧固醇受体肝脏X受体(LXR)α和LXRβ的直接靶标。高胆固醇饲料显著增加小鼠肝脏和肠道中ABCG5/G8基因的表达。使用LXR及其异二聚体伙伴维甲酸X受体的合成配体也观察到了这种增加。LXR激动剂处理的小鼠组织的原位杂交分析表明，ABCG5/G8 mRNA定位于肝细胞和肠细胞，并随着LXR的激活而增加。此外，LXR激动剂作用于空肠肠上皮细胞后，LXR靶基因ABCA1的表达也显著上调，此前该基因与胆固醇吸收的控制有关。在缺乏LXRs的小鼠中没有观察到ABC转运蛋白基因表达的这些变化。此外，在大鼠肝癌细胞系FTO2B中，依赖LXR的ABCG5/G8基因的转录是放线菌酮抗性的，表明这些基因直接受LXR调控。ABCG5和ABCG8被添加到越来越多的LXR靶基因列表中，进一步支持了LXR作为类固醇传感器来协调调节类固醇分解代谢、储存、外排和消除的概念。
Mutations in the ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 have recently been shown to cause the autosomal recessive disorder sitosterolemia. Here we demonstrate that the ABCG5 and ABCG8 genes are direct targets of the oxysterol receptors liver X receptor (LXR) alpha and LXRbeta. Diets containing high cholesterol markedly increased the expression of ABCG5/G8 mRNA in mouse liver and intestine. This increase was also observed using synthetic ligands of LXR and its heterodimeric partner, the retinoid X receptor. In situ hybridization analyses of tissues from LXR agonist-treated mice revealed that ABCG5/G8 mRNA is located in hepatocytes and enterocytes and is increased upon LXR activation. In addition, expression of the LXR target gene ABCA1, previously implicated in the control of cholesterol absorption, was also dramatically up-regulated in jejunal enterocytes upon exposure to LXR agonists. These changes in ABC transporter gene expression were not observed in mice lacking LXRs. Furthermore, in the rat hepatoma cell line FTO2B, LXR-dependent transcription of the ABCG5/G8 genes was cycloheximide-resistant, indicating that these genes are directly regulated by LXRs. The addition of ABCG5 and ABCG8 to the growing list of LXR target genes further supports the notion that LXRs serve as sterol sensors to coordinately regulate sterol catabolism, storage, efflux, and elimination.