HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis

Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement of KCs with bone marrow-derived recruited hepatic macrophages (RHMs) that highly e...

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Bibliographic Details
Published in:	Science translational medicine Vol. 16; no. 764; p. eadi0284
Main Authors:	Jeelani, Ishtiaq, Moon, Jae-Su, da Cunha, Flavia Franco, Nasamran, Chanond A, Jeon, Seokhyun, Zhang, Xinhang, Bandyopadhyay, Gautam K, Dobaczewska, Katarzyna, Mikulski, Zbigniew, Hosseini, Mojgan, Liu, Xiao, Kisseleva, Tatiana, Brenner, David A, Singh, Seema, Loomba, Rohit, Kim, Minkyu, Lee, Yun Sok
Format:	Journal Article
Language:	English
Published:	United States 11-09-2024
Subjects:	Animals Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - metabolism Basic Helix-Loop-Helix Transcription Factors - metabolism Cell Death Humans Inflammation - metabolism Inflammation - pathology Kupffer Cells - metabolism Liver - metabolism Liver - pathology Lysosomes - metabolism Macrophage Activation Macrophages - metabolism Mice Mice, Inbred C57BL Mitochondria - metabolism Non-alcoholic Fatty Liver Disease - metabolism Non-alcoholic Fatty Liver Disease - pathology Phagocytosis Reactive Oxygen Species - metabolism TOR Serine-Threonine Kinases - metabolism
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Summary:	Proinflammatory hepatic macrophage activation plays a key role in the development of nonalcoholic steatohepatitis (NASH). This involves increased embryonic hepatic Kupffer cell (KC) death, facilitating the replacement 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 hypoxia-inducible factor 2α (HIF-2α) mediates NASH-associated decreased KC growth and efferocytosis by enhancing lysosomal stress. At the molecular level, HIF-2α stimulated mammalian target of rapamycin (mTOR)- and extracellular signal-regulated kinase-dependent inhibitory transcription factor EB (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-2α-dependent TFEB regulation only occurred in KCs but not RHMs. Instead, in RHMs, HIF-2α promoted mitochondrial reactive oxygen species production and proinflammatory activation by increasing ANT2 expression and mitochondrial permeability transition. Consequently, myeloid lineage-specific or KC-specific HIF-2α depletion or the inhibition of mTOR-dependent TFEB inhibition using antisense oligonucleotide treatment protected against the development of NASH in mice. Moreover, treatment with an HIF-2α-specific inhibitor reduced inflammatory and fibrogenic gene expression in human liver spheroids cultured under a NASH-like condition. Together, our results suggest that macrophage subtype-specific effects of HIF-2α collectively contribute to the proinflammatory activation of liver macrophages, leading to the development of NASH.
ISSN:	1946-6242
DOI:	10.1126/scitranslmed.adi0284