Centre for Endocrinology, William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London EC1M 6BQ, UK.
Department of Chemistry and Molecular Biology, University of Gothenburg, 405 30 Göteborg, Sweden.
Cells. 2024 Jul 25;13(15):1255. doi: 10.3390/cells13151255.
Cholesterol is required to maintain the functional integrity of cellular membrane systems and signalling pathways, but its supply must be closely and dynamically regulated because excess cholesterol is toxic. Sterol regulatory element-binding protein 2 (SREBP2) and the ER-resident protein HMG-CoA reductase (HMGCR) are key regulators of cholesterol biosynthesis. Here, we assessed the mechanistic aspects of their regulation in hepatic cells. Unexpectedly, we found that the transcriptionally active fragment of SREBP2 (N-SREBP2) was produced constitutively. Moreover, in the absence of an exogenous cholesterol supply, nuclear N-SREBP2 became resistant to proteasome-mediated degradation. This resistance was paired with increased occupancy at the promoter and expression. Inhibiting nuclear N-SREBP2 degradation did not increase RNA levels; this increase required cholesterol depletion. Our findings, combined with previous physiological and biophysical investigations, suggest a new model of SREBP2-mediated regulation of cholesterol biosynthesis in the organ that handles large and rapid fluctuations in the dietary supply of this key lipid. Specifically, in the nucleus, cholesterol and the ubiquitin-proteasome system provide a short-loop system that modulates the rate of cholesterol biosynthesis via regulation of nuclear N-SREBP2 turnover and expression. Our findings have important implications for maintaining cellular cholesterol homeostasis and lowering blood cholesterol via the SREBP2-HMGCR axis.
胆固醇对于维持细胞膜系统和信号通路的正常功能是必需的，但胆固醇的供应必须受到严格和动态的调节，因为过量的胆固醇是有毒的。固醇调节元件结合蛋白 2（SREBP2）和内质网驻留蛋白 HMG-CoA 还原酶（HMGCR）是胆固醇生物合成的关键调节因子。在这里，我们评估了它们在肝细胞中的调节机制。出乎意料的是，我们发现转录活性片段的 SREBP2（N-SREBP2）是组成性产生的。此外，在没有外源性胆固醇供应的情况下，核 N-SREBP2 对蛋白酶体介导的降解变得具有抗性。这种抗性伴随着在启动子上的增加占有率和 的表达。抑制核 N-SREBP2 的降解不会增加 的 RNA 水平；这种增加需要胆固醇耗竭。我们的发现，结合以前的生理和生物物理研究，提出了一个新的 SREBP2 介导的胆固醇生物合成调节模型，该模型在处理这种关键脂质的饮食供应的大而快速波动的器官中。具体来说，在核内，胆固醇和泛素-蛋白酶体系统提供了一个短回路系统，通过调节核 N-SREBP2 的周转率和 的表达来调节胆固醇生物合成的速度。我们的发现对于通过 SREBP2-HMGCR 轴维持细胞胆固醇稳态和降低血液胆固醇具有重要意义。
