PXD040457-1

PXD040457 is an original dataset announced via ProteomeXchange.

Title	HIF-2a drives hepatic Kupffer cell death and liver inflammation in nonalcoholic steatohepatitis
Description	Proinflammatory activation of hepatic macrophages plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the placement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly express proinflammatory genes. Moreover, phago/efferocytic activity of KCs is diminished in NASH, enhancing liver inflammation. However, the molecular mechanisms underlying these changes in KCs are not known. Here, we show that HIF-2a mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2a stimulated mTOR and ERK-dependent inhibitory TFEB phosphorylation, leading to decreased lysosomal and phagocytic gene expression. With increased metabolic stress and phago/efferocytic burden in NASH, these changes were sufficient to increase lysosomal stress, causing decreased efferocytosis and lysosomal cell death. Of interest, HIF-2a-dependent TFEB regulation only occurred in KCs, but not in RHMs. Instead, in RHMs, HIF-2a promoted mtROS production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Taken together, our results suggest that macrophage subtype-specific effects of HIF-2a collectively contributes to the proinflammatory activation of liver macrophages, leading to the development of NASH.
HostingRepository	PRIDE
AnnounceDate	2025-05-06
AnnouncementXML	Submission_2025-05-06_09:24:50.273.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Minkyu Kim
SpeciesList	scientific name: Mus musculus (Mouse); NCBI TaxID: 10090;
ModificationList	phosphorylated residue
Instrument	Orbitrap Exploris 480

Revision	Datetime	Status	ChangeLog Entry
0	2023-02-27 06:15:47	ID requested
⏵ 1	2025-05-06 09:24:51	announced

Jeelani I, Moon JS, da Cunha FF, Nasamran CA, Jeon S, Zhang X, Bandyopadhyay GK, Dobaczewska K, Mikulski Z, Hosseini M, Liu X, Kisseleva T, Brenner DA, Singh S, Loomba R, Kim M, Lee YS, drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis. Sci Transl Med, 16(764):eadi0284(2024) [pubmed]

10.1126/scitranslmed.adi0284;

submitter keyword: Nonalcoholic Fatty Liver Disease (NAFLD), Macrophage,Obesity, Proinflammatory Macrophage Activation, Nonalcoholic Steatohepatitis (NASH), Inflammation/Metaflammation, HIF-2a, Kupffer Cell Death, Hypoxia

Minkyu Kim
contact affiliation	Department of Biochemistry and Structural Biology, UT Health San Antonio, San Antonio, TX 78922
contact email	mkkim20@gmail.com
lab head
Minkyu Kim
contact affiliation	UT Health San Antonio
contact email	mkkim20@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD040457
     1. Label: PRIDE project
     2. Name: HIF-2a drives hepatic Kupffer cell death and liver inflammation in nonalcoholic steatohepatitis