Regulation of Circadian Metabolism by the Hepatic Transcription Factor CREBH

项目摘要 昼夜节律失调与人类代谢疾病密切相关，如2型糖尿病， 心血管疾病和非酒精性脂肪肝（NAFLD）。由于现代生活方式， 不规则的昼夜节律对公共卫生有巨大的影响。虽然取得了很大进展， 在理解昼夜节律和新陈代谢之间的联系时， 昼夜节律调节剂调节代谢节律及其在代谢紊乱进展中的作用 仍有待进一步阐明。在上一个资助周期，我们定义了内质网（ER）居民， 一种名为CREBH（环AMP反应元件结合蛋白H）的肝特异性转录因子， 由多种炎症和代谢信号激活，作为肝脏能量的关键调节器发挥作用 新陈代谢.最近，我们已经积累了强有力的初步证据，CREBH功能作为一个器官- 特定的昼夜调节器，对保持能量稳态的节律性至关重要。在昼夜节律中， 在一个循环中，肝脏中的CREBH激活由核心时钟振荡器BMAL 1调节，并且激活的CREBH 与关键的昼夜代谢调节剂相互作用，以调节脂质和葡萄糖稳态的昼夜节律。 CREBH缺陷小鼠表现出脂质和葡萄糖节律性受损以及代谢反应改变， 并且易发生肝脂肪变性和高脂血症。这些观察导致我们 核心假设CREBH作为肝脏中整合昼夜节律的关键转录调节因子发挥作用 调节肝脏能量平衡。CREBH调节的肝脏能量节律性的破坏有助于 在代谢性饮食或轮班工作/喂养条件下，可能导致或放大NAFLD和高脂血症。测试 这个假设，我们将利用分子和细胞的方法，动物遗传学，昼夜代谢， 研究以解决CREBH调节的分子机制和病理生理学意义， 代谢节律性在NAFLD和高脂血症的进展。我们将寻求两个互补的 具体目的：目的1，确定CREBH的昼夜节律调节及其在维持昼夜节律中的作用。 在生理和病理环境中能量稳态的节律性;目的2， CREBH将昼夜节律调节整合到肝脏能量代谢的分子机制。内 在资助期内，我们预计将提供重要的见解的分子机制， 整合昼夜节律调节能量代谢，其中CREBH发挥关键作用，并决定 代谢综合征分子网络的病理生理学影响我们的研究计划将 显著扩展了我们对应激诱导反式激活因子之间功能关系的理解， 以及它们在调节昼夜代谢中的相互作用和协同作用。的结果 我们的研究对预防和治疗代谢性疾病具有重要意义。

PROJECT SUMMARY Dysregulated circadian rhythm is closely associated with human metabolic disease, such as type-2 diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Due to the modern life style, the problem of irregular circadian rhythm has enormous impact in public health. Although considerable progress has been made in understanding the connection between circadian rhythm and metabolism, the mechanisms by which circadian regulators modulate metabolic rhythmicity and its impact in the progression of metabolic disorders remain to be further elucidated. During the last funding cycle, we defined an endoplasmic reticulum (ER)-resident, liver-specific transcription factor named CREBH (cyclic-AMP-response element-binding protein H) that can be activated by a variety of inflammatory and metabolic signals to function as a key regulator of hepatic energy metabolism. Recently, we have accumulated strong preliminary evidence that CREBH functions as an organ- specific, diurnal regulator that is critical for preserving the rhythmicity of energy homeostasis. During the circadian cycle, CREBH activation in the liver is regulated by the core clock oscillator BMAL1, and activated CREBH interacts with the key circadian metabolic regulators to regulate diurnal rhythm of lipid and glucose homeostasis. CREBH-deficient mice display impaired rhythmic profiles of lipids and glucose and altered metabolic responses, and are susceptible to the development of hepatic steatosis and hyperlipidemia. These observations led to our central hypothesis that CREBH functions as a key transcriptional regulator in the liver that integrates circadian regulation to hepatic energy homeostasis. Disruption of CREBH-regulated hepatic energy rhythmicity contributes to or amplifies NAFLD and hyperlipidemia under the metabolic diet or shift working/feeding conditions. To test this hypothesis, we will utilize molecular and cellular approaches, animal genetics, and circadian metabolic studies to address the molecular mechanism and pathophysiological significance for CREBH-regulated metabolic rhythmicity in the progression of NAFLD and hyperlipidemia. We will pursue two complementary specific aims: Aim 1, to determine the circadian regulation of CREBH and its role in preserving circadian rhythmicity of energy homeostasis in both physiological and pathological settings; Aim 2, to decipher the molecular mechanisms by which CREBH integrates circadian regulation to hepatic energy metabolism. Within the funding period, we anticipate providing significant insights into the molecular mechanism underlying the integration of circadian regulation to energy metabolism, in which CREBH plays a key role, and determining the pathophysiological impact of the defined molecular network in metabolic syndrome. Our proposed research will significantly extend our understanding of the functional relationship between stress-inducible trans-activators and nuclear receptors and their interaction and synergism in regulating circadian metabolism. The findings from our proposed research will have important implications in the prevention and treatment of metabolic disease.