NRF1 是内质网膜传感器，是胆固醇稳态的核心。

NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis.

机构信息

Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.

Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.

出版信息

Cell. 2017 Nov 16;171(5):1094-1109.e15. doi: 10.1016/j.cell.2017.10.003.

DOI:10.1016/j.cell.2017.10.003

PMID:29149604

Abstract

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.

摘要

胆固醇是一种关键的营养物质，由于其独特的挑战性物理特性，在 ER 中需要严格限制。虽然 ER 抵御胆固醇不足的机制已经得到很好的描述，但 ER 如何感知和有效抵御胆固醇过多仍不清楚。在这里，我们确定 ER 结合转录因子红细胞系相关因子-1（Nrf1/Nfe2L1）是该过程的关键介质。我们表明，Nrf1 通过一个定义的结构域直接结合并特异性感知 ER 中的胆固醇，胆固醇调节 Nrf1 的周转率、加工、定位和活性。在 Nrf1 缺陷中，体内胆固醇挑战会导致大量肝胆固醇积累和损伤，而通过外源替换 Nrf1 可以挽救这种损伤。这种 Nrf1 介导的机制涉及抑制 CD36 驱动的炎症信号和解除肝 X 受体活性的抑制。这些发现揭示了 Nrf1 作为胆固醇动态平衡的守护者和细胞内胆固醇过多的适应性反应的核心组成部分。