Regulation of Circadian Metabolism by the Hepatic Transcription Factor CREBH

项目总结 昼夜节律失调与人类代谢性疾病密切相关，如2型糖尿病， 心血管疾病和非酒精性脂肪肝(NAFLD)。由于现代的生活方式，这个问题 昼夜节律不规律对公众健康有巨大影响。尽管已经取得了相当大的进展 在理解昼夜节律和新陈代谢之间的联系方面取得了进展，通过这些机制 昼夜节律调节代谢节律性及其在代谢紊乱进展中的作用 仍有待进一步阐明。在上一个资金周期中，我们定义了内质网(ER)驻留， 肝脏特异性转录因子CREBH(环磷酸腺苷反应元件结合蛋白H)，可以是 被多种炎症和代谢信号激活，发挥肝脏能量的关键调节作用 新陈代谢。最近，我们积累了强有力的初步证据，证明CREBH作为一个器官发挥作用- 特定的、昼夜节律的调节器，对于保持能量动态平衡的节律性至关重要。在昼夜节律中 周期，肝脏中CREBH的激活由核心时钟振荡器BMAL1调节，并激活CREBH 与关键的昼夜代谢调节器相互作用，调节血脂和葡萄糖的昼夜节律和动态平衡。 CREBH基因缺陷的小鼠表现出血脂和血糖节律性受损，代谢反应改变， 易发生肝脏脂肪变性和高脂血症。这些观察结果导致了我们 中心假说：CREBH在肝脏中起着整合昼夜节律的关键转录调节作用 调节肝脏能量动态平衡。CREBH调节的肝脏能量节律性的破坏 在代谢性饮食或倒班工作/喂养条件下导致或放大NAFLD和高脂血症。为了测试 在这个假设中，我们将利用分子和细胞方法、动物遗传学和昼夜代谢。 CREBH调控的分子机制及其病理生理意义的研究 非酒精性脂肪肝和高脂血症进展中的代谢节律性。我们将追求两个互补 具体目标：目标1，确定CREBH的昼夜节律及其在维持昼夜节律中的作用 生理和病理环境中能量动态平衡的节律性；目标2，破译 CREBH结合昼夜节律调节肝脏能量代谢的分子机制。在 在资助期，我们预计将对潜在的分子机制提供重要的见解 昼夜节律调节与能量代谢的整合，其中CREBH发挥关键作用，并决定 明确的分子网络在代谢综合征中的病理生理学影响。我们提议的研究将 显著扩展了我们对应激诱导反式激活剂之间的功能关系的理解 和核受体及其在调节昼夜新陈代谢中的相互作用和协同作用。调查结果来自 我们提出的研究将对代谢性疾病的预防和治疗具有重要的意义。

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.