PXD032069

PXD032069 is an original dataset announced via ProteomeXchange.

Title	Complementary gene regulation by NRF1 and NRF2 safeguard hepatic cholesterol detoxification
Description	Metabolic-associated steatohepatitis is a progressive fatty liver disease caused, in part, by hepatocyte stress linked to cholesterol overload. Counteracting this stress may be beneficial but there is insufficient understanding of underlying stress defenses to develop a therapeutic strategy. Here, we aimed to elucidate how stress-adaptive transcription factors, nuclear factor erythroid 2 related factor-1 (NRF1) and -2 (NRF2), counteract hepatic cholesterol overload and determine whether they function cooperatively. C57bl/6 mice were fed high fat, fructose, and cholesterol diet (HFFC). Expression profiling and phenotypic analyses were done on liver of mice with adult-onset and hepatocyte-specific deficiency of NRF1, NRF2, or both, and results compared to control. Chromatin immunoprecipitation (ChIP) sequencing was done and combined with expression profiles to identify genes that NRF1 and NRF2 interact with and regulate in vivo. Three weeks HFFC diet feeding to mice with NRF1 and NRF2 deficiency caused severe steatohepatitis and increased hepatic cholesterol storage. These outcomes did not occur in single gene-deficient mice or control. Expression profiling at a time preceding hepatic cholesterol overload and ChIP sequencing profiling revealed complementary gene regulation by NRF1 and NRF2 to promote cholesterol excretion and mitigate hazardous metabolic biproducts generated from converting cholesterol to bile acid. Consequently, combined gene deficiency, and not single-gene deficiency, increased liver oxidized protein level, decreased cholesterol in bile, and increased unconjugated bile acid in liver and bile. We discover, for the first time, that NRF1 and NRF2 work together to protect liver against damaging effects of excess cholesterol. Targeting these combined actions may prove an effective therapeutic strategy
HostingRepository	PRIDE
AnnounceDate	2023-03-22
AnnouncementXML	Submission_2023-03-22_09:50:09.873.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	SadhnaPhanse
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	No PTMs are included in the dataset
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-03-05 04:58:07	ID requested
⏵ 1	2023-03-22 09:50:10	announced

Dataset with its publication pending

submitter keyword: Mouse, obesity, NRF2, NRF1, Nuclear factor erythroid 2 related factor

Scott B.Widenmaier
contact affiliation	Department of Anatomy, Physiology, and Pharmacology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
contact email	scott.widenmaier@usask.ca
lab head
SadhnaPhanse
contact affiliation	University of Toronto; University of Regina
contact email	srphanse@gmail.com
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/03/PXD032069

PRIDE project URI

• PRIDE
  1. PXD032069
     1. Label: PRIDE project
     2. Name: Complementary gene regulation by NRF1 and NRF2 safeguard hepatic cholesterol detoxification