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.
Pubmed ID: 29149604 RIS Download
Publication data is provided by the National Library of Medicine ® and PubMed ®. Data is retrieved from PubMed ® on a weekly schedule. For terms and conditions see the National Library of Medicine Terms and Conditions.
A commercial graphing software company that offers scientific software for statistical analyses, curve fitting and data analysis. It offers four programs: Prism, InStat, StatMate and QuickCalcs.
View all literature mentionsCenter that produces knockout mice and carries out high-throughput phenotyping of each line in order to determine function of every gene in mouse genome. These mice will be preserved in repositories and made available to scientific community representing valuable resource for basic scientific research as well as generating new models for human diseases.
View all literature mentionsThis polyclonal targets IgG (H+L)
View all literature mentionsThis polyclonal secondary targets IgG (H+L)
View all literature mentionsThis polyclonal targets beta Tubulin (H-235)
View all literature mentionsThis polyclonal targets goat anti-rabbit IgG-HRP
View all literature mentionsThis monoclonal targets PDI
View all literature mentionsThis polyclonal targets Phospho-SAPK/JNK (Thr183/Tyr185)
View all literature mentionsThis monoclonal targets NRF2 (D1C9) Rabbit mAb
View all literature mentionsThis monoclonal targets TCF11/NRF1 (D5B10) Rabbit mAb
View all literature mentionsThis polyclonal targets Mouse IgG
View all literature mentionsThis polyclonal targets SAPK/JNK
View all literature mentionsThis monoclonal targets HA-Tag
View all literature mentionsThis monoclonal targets Cyclin D1
View all literature mentionsThis monoclonal targets CREB
View all literature mentions