PXD035243

PXD035243 is an original dataset announced via ProteomeXchange.

Title	Hepatic Sel1L-Hrd1 ER-associated degradation deficiency leads to intrahepatic cholestasis in mice
Description	The liver is the central organ critically regulating the balance of the metabolically potent yet toxic bile acids in the body. While genomic association studies have pointed to hepatic Sel1L – a critical component of mammalian Hrd1 ER-associated degradation (ERAD) machinery – as an influencer of serum bile acid levels, physiological relevance and mechanistic insights of ERAD in bile homeostasis remain unexplored. Using hepatocyte-specific Sel1L-deficient mouse models, we report that hepatic Sel1L-Hrd1 ERAD critically manages bile homeostasis in the body. Mice with hepatocyte-specific Sel1L developed intrahepatic cholestasis, with significant overload of bile acids in the liver and circulation under basal condition, and were hypersensitive to dietary bile acid challenge. By contrast, biliary bile acid and phosphatidylcholine levels were reduced, pointing to an export defect from hepatocytes. Unbiased proteomics analysis followed by biochemical assays revealed significant accumulation of the bile-stabilizing phosphatidylcholine exporter ATP-binding cassette 4 (Abcb4) in the ER of Sel1L-deficient livers, a gene associated with Progressive Familial Intrahepatic Cholestasis type III. Indeed, Abcb4 was a substrate of Sel1L-Hrd1 ERAD. Hence, hepatic Sel1L-Hrd1 ERAD maintains bile equilibrium via quality control of Abcb4 maturation in the ER.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_08:38:11.992.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Asmita Bhattacharya
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; deamidated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion

Revision	Datetime	Status	ChangeLog Entry
0	2022-07-11 08:33:07	ID requested
1	2023-03-10 23:15:56	announced
⏵ 2	2023-11-14 08:38:14	announced	2023-11-14: Updated project metadata.

Bhattacharya A, Wei J, Song W, Gao B, Tian C, Wu SA, Wang J, Chen L, Fang D, Qi L, SEL1L-HRD1 ER-associated degradation suppresses hepatocyte hyperproliferation and liver cancer. iScience, 25(10):105183(2022) [pubmed]

submitter keyword: bile, liver, cholestasis, progressive familial intrahepatic cholestasis, Abcb4,Sel1L-Hrd1 ERAD

Ling Qi
contact affiliation	Professor, Molecular & Integrative Physiology, University of Michigan, Ann Arbor
contact email	lingq@med.umich.edu
lab head
Asmita Bhattacharya
contact affiliation	Stanford University
contact email	asmitab@stanford.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD035243
     1. Label: PRIDE project
     2. Name: Hepatic Sel1L-Hrd1 ER-associated degradation deficiency leads to intrahepatic cholestasis in mice