Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
Department of Pediatrics, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
FASEB J. 2019 Jul;33(7):7896-7914. doi: 10.1096/fj.201802528R. Epub 2019 Mar 26.
Autophagy, a lysosomal degradative pathway in response to nutrient limitation, plays an important regulatory role in lipid homeostasis upon energy demands. Here, we demonstrated that the endoplasmic reticulum-tethered, stress-sensing transcription factor cAMP-responsive element-binding protein, hepatic-specific (CREBH) functions as a major transcriptional regulator of hepatic autophagy and lysosomal biogenesis in response to nutritional or circadian signals. CREBH deficiency led to decreased hepatic autophagic activities and increased hepatic lipid accumulation upon starvation. Under unfed or during energy-demanding phases of the circadian cycle, CREBH is activated to drive expression of the genes encoding the key enzymes or regulators in autophagosome formation or autophagic process, including microtubule-associated protein 1B-light chain 3, autophagy-related protein (ATG)7, ATG2b, and autophagosome formation Unc-51 like kinase 1, and the genes encoding functions in lysosomal biogenesis and homeostasis. Upon nutrient starvation, CREBH regulates and interacts with peroxisome proliferator-activated receptor α (PPARα) and PPARγ coactivator 1α to synergistically drive expression of the key autophagy genes and transcription factor EB, a master regulator of lysosomal biogenesis. Furthermore, CREBH regulates rhythmic expression of the key autophagy genes in the liver in a circadian-dependent manner. In summary, we identified CREBH as a key transcriptional regulator of hepatic autophagy and lysosomal biogenesis for the purpose of maintaining hepatic lipid homeostasis under nutritional stress or circadian oscillation.-Kim, H., Williams, D., Qiu, Y., Song, Z., Yang, Z., Kimler, V., Goldberg, A., Zhang, R., Yang, Z., Chen, X., Wang, L., Fang, D., Lin, J. D., Zhang, K. Regulation of hepatic autophagy by stress-sensing transcription factor CREBH.
自噬是一种溶酶体降解途径，可响应营养限制，在能量需求时对脂质动态平衡发挥重要调节作用。在这里，我们证明了内质网连接的应激感应转录因子 cAMP 反应元件结合蛋白，肝特异性（CREBH）作为肝自噬和溶酶体生物发生的主要转录调节剂，响应营养或昼夜信号。CREBH 缺乏导致饥饿时肝自噬活性降低和肝脂质积累增加。在未进食或昼夜周期的能量需求阶段，CREBH 被激活以驱动自噬体形成或自噬过程中的关键酶或调节剂的基因表达，包括微管相关蛋白 1B-轻链 3、自噬相关蛋白（ATG）7、ATG2b 和自噬体形成 UNC-51 样激酶 1，以及编码溶酶体生物发生和动态平衡功能的基因。在营养饥饿时，CREBH 调节并与过氧化物酶体增殖物激活受体 α（PPARα）和 PPARγ 共激活物 1α相互作用，协同驱动关键自噬基因和转录因子 EB 的表达，后者是溶酶体生物发生的主要调节剂。此外，CREBH 以昼夜依赖的方式调节肝脏中关键自噬基因的节律表达。总之，我们确定 CREBH 是肝自噬和溶酶体生物发生的关键转录调节剂，目的是在营养应激或昼夜振荡下维持肝脂质动态平衡。-Kim，H.，Williams，D.，Qiu，Y.，Song，Z.，Yang，Z.，Kimler，V.，Goldberg，A.，Zhang，R.，Yang，Z.，Chen，X.，Wang，L.，Fang，D.，Lin，J. D.，Zhang，K. 应激感应转录因子 CREBH 调节肝自噬。
