Cell
Volume 171, Issue 5, 16 November 2017, Pages 1094-1109.e15
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Article
NRF1 Is an ER Membrane Sensor that Is Central to Cholesterol Homeostasis

https://doi.org/10.1016/j.cell.2017.10.003Get rights and content
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Highlights

  • Endoplasmic reticulum (ER) is vulnerable to stresses imposed by excess cholesterol

  • Nrf1 binds and senses excess cholesterol in ER membrane to protect from such stress

  • Nrf1-deficient liver massively accumulates cholesterol, resulting in liver disease

  • Nrf1 protects liver by suppressing inflammation and promoting cholesterol excretion

Summary

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.

Keywords

cholesterol
metabolism
endoplasmic reticulum
stress
inflammation
Nrf1
Nfe2L1
immunometabolism
liver

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