Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging biophysical properties. While the mechanisms by which the ER defends against cholesterol insufficiency are well described, it remains unclear how the ER senses and effectively defends against cholesterol excess. Here, we identify the ER-bound transcription factor nuclear factor erythroid 2 related factor-1, Nrf1/Nfe2L1, as a critical mediator of this process. We show that Nrf1 directly binds to and specifically senses cholesterol in the ER through a defined domain and that cholesterol regulates Nrf1 turnover, processing, localization, and activity. In Nrf1 deficiency, in vivo cholesterol challenges induce massive hepatic cholesterol accumulation and damage, which is rescued by replacing Nrf1 exogenously. This Nrf1-mediated mechanism involves the suppression of CD36-driven inflammatory signaling and derepression of liver X receptor activity. These findings reveal Nrf1 as a guardian of cholesterol homeostasis and a core component of adaptive responses to excess cellular cholesterol.

中文翻译：

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NRF1是一种ER膜传感器，对胆固醇体内平衡至关重要。

胆固醇是一种至关重要的营养素，由于其独特的具有挑战性的生物物理特性，因此需要在内质网（ER）中严格限制。尽管已很好地描述了ER防御胆固醇不足的机制，但仍不清楚ER如何感知和有效防御胆固醇过多。在这里，我们确定ER绑定转录因子核因子红系2相关因子-1，Nrf1 / Nfe2L1，作为此过程的关键介体。我们显示，Nrf1直接通过定义的域与ER中的胆固醇结合并特异性感知胆固醇，并且胆固醇调节Nrf1的营业额，加工，定位和活性。在Nrf1缺乏症中，体内胆固醇的挑战引起大量肝胆固醇的积累和损害，这可以通过外源性替代Nrf1来挽救。这种Nrf1介导的机制涉及CD36驱动的炎症信号的抑制和肝X受体活性的抑制。这些发现揭示了Nrf1是胆固醇稳态的守卫者，也是对过量细胞胆固醇的适应性反应的核心组成部分。