LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport
LXR (liver X receptor) and HNF-4 (hepatocyte nuclear factor-4): key regulators in reverse cholesterol transport
复制标题
DOI：
10.1042/bst0320092
复制
发表时间：
2004-02-01
影响因子：
3.9
通讯作者：
Galli, G
中科院分区：
文献类型：
--
作者：
Crestani, M;De Fabiani, E;Galli, G
胆固醇体内平衡是这种分子的摄入和处置之间的微调的结果。血液中高水平的胆固醇是有害的，因为它们可能导致血管壁中的过度积累，这是一种易诱发动脉粥样硬化病变发展的条件。胆固醇从血管壁中移除，并通过称为胆固醇逆向转运的过程转运到肝脏。核受体是调节胆固醇逆向转运不同步骤的基因的最重要的转录因子之一。在这里，我们讨论了核受体LXR（肝X受体）和HNF-4 α（肝细胞核因子-4 α）在胆固醇逆向转运的不同步骤中的作用。LXR控制胆固醇从巨噬细胞流出及其转运到肝脏的关键基因的转录，如ABCA 1（ATP结合盒A1）、CYP 27 A1（固醇27-羟化酶）、CLA-1（清道夫受体B1型）和载脂蛋白E。存在于氧化低密度脂蛋白和促炎细胞因子中的一些oxystefols通过拮抗该受体的活化剂的作用来调节LXR的活性，从而促进巨噬细胞中的胆固醇积累。胆汁酸合成是胆固醇逆向转运的最后一步，在肝脏特异性细胞色素P450胆固醇7 α-羟化酶（CYP 7A 1）（该代谢途径的限速酶）水平上受几种核受体的转录调控。胆汁酸通过肝肠循环返回肝脏，通过胆汁酸传感器法尼醇X受体和HNF-4 α下调CYP 7A 1转录。基于这些证据，这些核受体是用于治疗和预防动脉粥样硬化疾病的新药的候选靶点。
Cholesterol homoeostasis is the result of the fine tuning between intake and disposal of this molecule. High levels of cholesterol in the blood are detrimental as they may lead to excessive accumulation in vessel walls, a condition predisposing to the development of atherosclerotic lesions. Cholesterol is removed from the vessel wall and transported to the liver through a process called reverse cholesterol transport. Nuclear receptors are among the most important transcription factors regulating genes involved in different steps of reverse cholesterol transport. Here, we discuss the role of the nuclear receptors LXR (liver X receptor) and HNF-4alpha (hepatocyte nuclear factor-4alpha) in different steps of reverse cholesterol transport. LXR controls the transcription of crucial genes in cholesterol efflux from macrophages and its transport to the liver, such as ABCA1 (ATP binding cassette A1), CYP27A1 (sterol 27-hydroxylase), CLA-1 (scavenger receptor type B1) and apolipoprotein E. Some oxystefols present in oxidized low-density lipoproteins and proinflammatory cytokines modulate the activity of LXR by antagonizing the effect of activators of this receptor, thus contributing to cholesterol accumulation in macrophages. Bile acid synthesis, which represents the final step of reverse cholesterol transport, is transcriptionally regulated by several nuclear receptors at the level of the liver-specific cytochrome P450 cholesterol 7alpha-hydroxylase (CYP7A1), the rate-limiting enzyme of this metabolic pathway. Bile acids returning to the liver through the enterohepatic circulation down-regulate CYP7A1 transcription via the bile acid sensors farnesoid X receptor and HNF-4alpha. Based on this evidence, these nuclear receptors are candidate targets of new drugs for the treatment and prevention of atherosclerotic disease.