PXD024717

PXD024717 is an original dataset announced via ProteomeXchange.

Title	UCP1-dependent depletion of liver extracellular succinate antagonizes inflammatory pathogenesis
Description	Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver pathology worldwide and is intimately linked with obesity and type 2 diabetes. Liver inflammation is a hallmark of NAFLD and is thought to contribute to tissue fibrosis and disease pathogenesis. Uncoupling protein 1 (UCP1) is exclusively expressed in brown and beige adipocytes and has been extensively studied for its capacity to elevate thermogenesis and reverse obesity. Here we identify an endocrine pathway regulated by UCP1 that antagonizes liver inflammation and pathology, independent of effects on obesity. We show that, without UCP1, brown and beige fat exhibit a diminished capacity to clear succinate from the circulation. Moreover, UCP1KO mice exhibit elevated extracellular succinate in liver tissue that drives inflammation through ligation of its cognate receptor succinate receptor 1 (SUCNR1) in liver-resident stellate cell and macrophage populations. Conversely, increasing brown and beige adipocyte content in mice antagonizes SUCNR1-dependent inflammatory signaling in the liver. We show that this UCP1-succinate-SUCNR1 axis is necessary to regulate liver immune cell infiltration and pathology, and systemic glucose intolerance in an obesogenic environment. As such, the therapeutic utility of brown and beige adipocytes, and UCP1, extends beyond thermogenesis and may be leveraged to antagonize NAFLD and SUCNR1-dependent liver inflammation.
HostingRepository	PRIDE
AnnounceDate	2022-02-17
AnnouncementXML	Submission_2022-02-16_23:15:05.340.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Haopeng Xiao
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	carbamoylated residue
Instrument	Orbitrap Eclipse

Revision	Datetime	Status	ChangeLog Entry
0	2021-03-14 23:51:55	ID requested
⏵ 1	2022-02-16 23:15:06	announced

Mills EL, Harmon C, Jedrychowski MP, Xiao H, Garrity R, Tran NV, Bradshaw GA, Fu A, Szpyt J, Reddy A, Prendeville H, Danial NN, Gygi SP, Lynch L, Chouchani ET, UCP1 governs liver extracellular succinate and inflammatory pathogenesis. Nat Metab, 3(5):604-617(2021) [pubmed]

submitter keyword: Liver, BAT, UCP1, inflammation, thermogenesis

Edward Chouchani
contact affiliation	Dana-Farber Cancer Institute/ Harvard Medical School
contact email	edwardt_chouchani@dfci.harvard.edu
lab head
Haopeng Xiao
contact affiliation	Dana-Farber Cancer Institute/Harvard Medical School
contact email	haopeng_xiao@dfci.harvard.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD024717
     1. Label: PRIDE project
     2. Name: UCP1-dependent depletion of liver extracellular succinate antagonizes inflammatory pathogenesis