REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis.
REV-ERBalpha participates in circadian SREBP signaling and bile acid homeostasis.
复制标题
DOI：
10.1371/journal.pbio.1000181
复制
发表时间：
2009-09
期刊：
影响因子：
9.8
通讯作者：
Schibler U
中科院分区：
文献类型：
--
作者：
Le Martelot G;Claudel T;Gatfield D;Schaad O;Kornmann B;Lo Sasso G;Moschetta A;Schibler U
核受体REV-ERBα影响斯特罗反应元件结合蛋白的每日活性，从而参与肝脏胆固醇和胆汁酸合成的昼夜节律控制。在哺乳动物中，行为和生理的许多方面，特别是细胞代谢，是由昼夜节律系统协调的。分子时钟被认为依赖于时钟基因表达的负反馈环，从而在转录调节蛋白的积累中产生振荡，例如孤儿受体REV-ERBα。然后，昼夜节律转录因子驱动时钟控制的输出基因的表达，例如编码酶和细胞新陈代谢调节器的基因。为了深入了解REV-ERBα的时钟输出功能，我们对野生型小鼠、REV-ERBα敲除小鼠或REV-ERBα过表达小鼠的肝脏RNA进行了全基因组转录组谱实验。在这些遗传功能丧失和功能获得实验的基础上，我们得出结论，REV-ERBα参与了类固醇调节元件结合蛋白活性的昼夜调节，从而参与了参与胆固醇和脂肪代谢的类固醇调节元件结合蛋白靶基因的日常表达。这种控制是通过Insig2的循环转录实现的，Insig2编码一种跨膜蛋白，将SREBP蛋白隔离到内质网膜上，从而干扰SREBPs在高尔基膜上的蛋白水解性激活。REV-ERBα还参与胆固醇-7α羟基酶的循环表达，该酶是胆固醇转化为胆汁酸的限速酶。我们的发现表明，这种控制作用是通过周期性产生的氧固醇刺激LXR核受体起作用的。总之，我们的研究表明，有节奏的胆固醇和胆汁酸代谢不仅仅是由交替的喂食-禁食周期驱动的，也是由REV-ERBα驱动的，REV-ERB是生物钟电路的一个组成部分。哺乳动物的昼夜节律系统有一个层次结构：大脑视交叉上核(SCN)中的一个中央起搏器同步存在于大多数外周细胞类型中的辅助振荡器。在SCN神经元和外周细胞中，昼夜节律振荡器被认为依赖于两个负反馈环路。一个主要的反馈环涉及两个隐花色素CRY1和CRY2以及两个周期蛋白PER1和PER2，这两个蛋白充当各自基因的转录抑制因子。一个辅助反馈环将转录激活剂CLOCK和BMAL1的表达和活性与隐花色素和周期蛋白的表达偶联。孤儿核受体REV-ERBα是这个辅助反馈环中的关键角色，因为它周期性地抑制BMal1转录。在肝脏中，分子时钟调节新陈代谢过程的时间门控。在这里，我们证明了肝细胞时钟参与控制胆固醇和胆汁酸的稳态。根据这一设想，REV-ERBα塑造了胰岛素诱导基因2(INSIG2)的昼夜表达模式，INSIG2是内质网的一种驻留蛋白，干扰了固醇反应元件结合蛋白(SREBPs)的蛋白分解激活。反过来，SREBPs控制在类固醇和脂肪酸合成中起关键作用的酶的有节奏的表达。Cyp7a1转录的关键激活剂是LXR核受体，其昼夜节律的产生可能导致LXR核受体的循环激活。细胞色素P7A1，也被称为胆固醇7α羟基酶，催化胆汁酸合成的限速步骤。
The nuclear receptor REV-ERBα shapes the daily activity profile of Sterol Response Element Binding Protein (SREBP) and thereby participates in the circadian control of cholesterol and bile acid synthesis in the liver. In mammals, many aspects of behavior and physiology, and in particular cellular metabolism, are coordinated by the circadian timing system. Molecular clocks are thought to rely on negative feedback loops in clock gene expression that engender oscillations in the accumulation of transcriptional regulatory proteins, such as the orphan receptor REV-ERBα. Circadian transcription factors then drive daily rhythms in the expression of clock-controlled output genes, for example genes encoding enzymes and regulators of cellular metabolism. To gain insight into clock output functions of REV-ERBα, we carried out genome-wide transcriptome profiling experiments with liver RNA from wild-type mice, Rev-erbα knock-out mice, or REV-ERBα overexpressing mice. On the basis of these genetic loss- and gain-of-function experiments, we concluded that REV-ERBα participates in the circadian modulation of sterol regulatory element-binding protein (SREBP) activity, and thereby in the daily expression of SREBP target genes involved in cholesterol and lipid metabolism. This control is exerted via the cyclic transcription of Insig2, encoding a trans-membrane protein that sequesters SREBP proteins to the endoplasmic reticulum membranes and thereby interferes with the proteolytic activation of SREBPs in Golgi membranes. REV-ERBα also participates in the cyclic expression of cholesterol-7α-hydroxylase (CYP7A1), the rate-limiting enzyme in converting cholesterol to bile acids. Our findings suggest that this control acts via the stimulation of LXR nuclear receptors by cyclically produced oxysterols. In conclusion, our study suggests that rhythmic cholesterol and bile acid metabolism is not just driven by alternating feeding–fasting cycles, but also by REV-ERBα, a component of the circadian clockwork circuitry. The mammalian circadian timing system has a hierarchical architecture: a central pacemaker in the brain's suprachiasmatic nucleus (SCN) synchronizes subsidiary oscillators present in most peripheral cell types. In both SCN neurons and peripheral cells, circadian oscillators are thought to rely on two negative feedback loops. A major feedback loop involves the two cryptochromes CRY1 and CRY2 and the two period proteins PER1 and PER2, which serve as transcriptional repressors for their own genes. An accessory feedback loop couples the expression and activity of the transcriptional activators CLOCK and BMAL1 to the expression of cryptochrome and period proteins. The orphan nuclear receptor REV-ERBα is a key player in this accessory feedback loop, in that it periodically represses Bmal1 transcription. In liver, molecular clocks mediate the temporal gating of metabolic processes. Here we demonstrate that hepatocyte clocks participate in the control of cholesterol and bile acid homeostasis. According to this scenario, REV-ERBα shapes the circadian expression pattern of insulin-induced gene 2 (INSIG2), a resident protein of the endoplasmic reticulum that interferes with the proteolytic activation of sterol response element binding proteins (SREBPs). In turn SREBPs govern the rhythmic expression of enzymes with key functions in sterol and fatty acid synthesis. The circadian production of sterols (in particular oxysterols) may engender the cyclic activation of LXR nuclear receptors, which serve as critical activators of Cyp7a1 transcription. CYP7A1, also known as cholesterol 7α-hydroxylase, catalyzes the rate-limiting step in bile acid synthesis.
登录
查看更多内容
DOI：
10.1073/pnas.95.11.5987
发表时间：
1998-05-26
影响因子：
11.1
作者：
Horton, JD;Bashmakov, Y;Shimano, H
通讯作者：
Shimano, H
影响因子：
9.2
作者：
Akhtar, RA;Reddy, AB;Kyriacou, CP
通讯作者：
Kyriacou, CP
影响因子：
5.8
作者：
Hubbell, E;Liu, WM;Mei, R
通讯作者：
Mei, R
DOI：
10.1073/pnas.0405067102
发表时间：
2005-01-18
影响因子：
11.1
作者：
Hegarty, BD;Bobard, A;Foufelle, F
通讯作者：
Foufelle, F
影响因子：
56.9
作者：
Balsalobre, A;Brown, SA;Schibler, U
通讯作者：
Schibler, U