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

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

Cell (2017-11-18)
Scott B Widenmaier, Nicole A Snyder, Truc B Nguyen, Alessandro Arduini, Grace Y Lee, Ana Paula Arruda, Jani Saksi, Alexander Bartelt, Gökhan S Hotamisligil
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.

MATERIALS
Product Number
Brand
Product Description

SAFC
SyntheChol® PLANT-DERIVED CHOLESTEROL, EMPROVE® EXPERT
Pricing and availability is not currently available.
Sigma-Aldrich
Magna ChIP® A/G Chromatin Immunoprecipitation Kit, Single day chromatin immunoprecipitation (ChIP) kit containing all necessary reagents to perform 22 individual chromatin immunoprecipitation (ChIP) reactions using magnetic A/G beads.
Pricing and availability is not currently available.
SAFC
SyntheChol® Synthetic Cholesterol, For Cell Culture, EMPROVE® EXPERT
Pricing and availability is not currently available.