Nuclear hormone receptors and cholesterol trafficking: the orphans find a new home
Nuclear hormone receptors and cholesterol trafficking: the orphans find a new home
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DOI：
10.1007/s00109-001-0318-y
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发表时间：
2002-03
期刊：
影响因子：
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通讯作者：
M. Fitzgerald;K. Moore;M. Freeman
中科院分区：
文献类型：
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作者：
M. Fitzgerald;K. Moore;M. Freeman
有许多稳态机制有助于调节人体细胞和血清胆固醇水平。我们对这种调节的大部分理解来自于对控制胆固醇合成和低密度脂蛋白摄取和降解的细胞途径的研究。控制整个动物胆固醇配置的生理学，包括负责膳食摄取胆固醇及其随后分解代谢为胆汁酸的分子机制，直到现在才被发现。本文综述了最近使用现代遗传技术和细胞生物学方法开始阐明体内胆固醇运输途径的研究。这项工作使人们认识到核激素受体网络，包括LXR、FXR、PPAR和RXR蛋白，通过对控制固醇代谢途径的基因的转录调节，在脂质代谢中起着关键作用。这些调控网络的一些主要下游靶点涉及ABC转运蛋白家族的成员，包括ABCA1、ABCG1、ABCG5、ABCG8、MDR3/Mdr2和SPGP/BSEP。这些转运蛋白通过尚未阐明的机制促进甾醇和胆脂穿过细胞膜的运动。通过靶向核激素受体的药物来操纵这些胆固醇运输途径的潜力已经引起了人们对其生物学的极大兴趣，毫无疑问，这将在未来几年引领人类疾病的新治疗方法。
There are many homeostatic mechanisms that contribute to the regulation of cellular and serum cholesterol levels in humans. Much of our understanding of this regulation arose from studies of the cellular pathways controlling cholesterol synthesis and the uptake and degradation of low-density lipoproteins. The physiology governing cholesterol disposition in whole animals, including the molecular mechanisms responsible for dietary uptake of cholesterol and its subsequent catabolism to bile acids, are only now being uncovered. This review summarizes recent studies that have used modern genetic techniques, as well as cell biological methods, to begin to elucidate the pathways responsible for cholesterol trafficking in vivo. This work has led to the realization that networks of nuclear hormone receptors, including the LXR, FXR, PPAR, and RXR proteins, play critical roles in lipid metabolism by virtue of their transcriptional regulation of the genes that control sterol metabolic pathways. Some of the major downstream targets of these regulatory networks involve members of the ABC transporter family, including ABCA1, ABCG1, ABCG5, ABCG8, MDR3/Mdr2, and SPGP/BSEP. These transporters contribute to the movement of sterols and biliary lipids across cellular membranes via mechanisms that have yet to be elucidated. The potential for manipulating these cholesterol trafficking pathways via drugs targeted to the nuclear hormone receptors has generated great interest in their biology and will undoubtedly lead to new therapeutic approaches to human disorders in the coming years.