CELL-D-16-01418R3_Widenmaier et al.

Cholesterol is a critical nutrient requiring tight constraint in the endoplasmic reticulum (ER) due to its uniquely challenging properties. While the mechanisms by which ER defends against cholesterol insufficiency are well described, it remains unclear how 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 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 de-repression 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.胆固醇是一种关键营养素，由于其独特的复杂特性，在内质网（ER）中需要受到严格的调控约束。尽管内质网抵御胆固醇缺乏的机制已被充分阐明，但内质网如何感知并有效应对胆固醇过量的问题仍不明确。本研究鉴定出内质网结合型转录因子核因子红细胞2相关因子1（Nrf1/Nfe2L1）是这一过程的关键介导因子。我们证实Nrf1可通过特定结构域直接结合并特异性感知内质网中的胆固醇，且胆固醇可调控Nrf1的周转、加工、定位及活性。在Nrf1缺失的情况下，体内胆固醇负荷刺激会诱导大量肝脏胆固醇蓄积与损伤，而外源性补充Nrf1可逆转这一表型。这一Nrf1介导的机制涉及抑制CD36驱动的炎症信号通路，并解除对肝X受体（liver X receptor, LXR）活性的抑制。这些发现揭示Nrf1是胆固醇稳态的守护者，亦是细胞应对过量胆固醇的适应性应答核心组分。