Henan Key Laboratory of Biological Psychiatry, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, Henan Province, China.
Department of Pharmacy, The Second Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453002, Henan Province, China.
Biochem Biophys Res Commun. 2021 Feb 19;541:90-94. doi: 10.1016/j.bbrc.2021.01.011. Epub 2021 Jan 20.
Chronic and excessive alcohol consumption leads to alcoholic liver disease (ALD). However, the molecular mechanisms in the regulation of ALD have not been fully deciphered. Liver lipid accumulation is an important research direction in ALD. In this study, the physiological role of nuclear factor Y (NF-Y) in ALD and the related mechanisms were investigated using murine hepatocytes and an ethanol-induced liver injury mouse model. In this study, ethanol promoted hepatic NF-Y expression in a mouse model and Hepa1-6 mouse hepatocytes. Lentivirus-mediated NF-Y overexpression in Hepa1-6 cells markedly increased sterol regulatory element binding protein 1 (SREBP1) and fatty acid synthase (FASN) expression compared with empty vector control cells. Conversely, CRISPR/Cas9-mediated knockdown of NF-Y subunit A (NF-YA) attenuated FASN and SREBP1 expression. Mechanistically, luciferase reporter gene assays and chromatin immunoprecipitation (ChIP) analysis indicated that NF-Y activates the transcription of SREBP1 by directly binding to the CCAAT regulatory sequence motif in the promoter. Overall, our results reveal a previously unrecognized physiological function of NF-Y in ALD by activating sterol regulatory element-binding protein 1 (SREBP1). Modulation of hepatic NF-Y expression may therefore offer an attractive therapeutic approach to manage ALD.
慢性和过度饮酒会导致酒精性肝病（ALD）。然而，调节 ALD 的分子机制尚未完全破译。肝脂质积累是 ALD 的一个重要研究方向。在这项研究中，使用鼠肝细胞和乙醇诱导的肝损伤小鼠模型研究了核因子 Y（NF-Y）在 ALD 中的生理作用及其相关机制。在这项研究中，乙醇在小鼠模型和 Hepa1-6 鼠肝细胞中促进了肝 NF-Y 的表达。与空载体对照细胞相比，慢病毒介导的 Hepa1-6 细胞中 NF-Y 的过表达显着增加了固醇调节元件结合蛋白 1（SREBP1）和脂肪酸合酶（FASN）的表达。相反，CRISPR/Cas9 介导的 NF-Y 亚基 A（NF-YA）敲低减弱了 FASN 和 SREBP1 的表达。从机制上讲，荧光素酶报告基因测定和染色质免疫沉淀（ChIP）分析表明，NF-Y 通过直接结合启动子中的 CCAAT 调节序列基序来激活 SREBP1 的转录。总的来说，我们的研究结果揭示了 NF-Y 在 ALD 中通过激活固醇调节元件结合蛋白 1（SREBP1）而发挥的先前未被认识到的生理功能。因此，调节肝 NF-Y 的表达可能为治疗 ALD 提供一种有吸引力的治疗方法。
