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HIF-2α drives hepatic Kupffer cell death and proinflammatory recruited macrophage activation in nonalcoholic steatohepatitis.
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.
Afiliación
  • Jeelani I; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Moon JS; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • da Cunha FF; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Nasamran CA; Center for Computational Biology & Bioinformatics, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Jeon S; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Zhang X; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Bandyopadhyay GK; Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Dobaczewska K; Microscopy and Histology Core Facility, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  • Mikulski Z; Microscopy and Histology Core Facility, La Jolla Institute for Immunology, La Jolla, CA 92037, USA.
  • Hosseini M; Department of Pathology, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
  • Liu X; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kisseleva T; Department of Surgery, University of California, San Diego, La Jolla, CA 92093, USA.
  • Brenner DA; Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
  • Singh S; Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Loomba R; Division of Gastroenterology, University of California, San Diego, La Jolla, CA 92093, USA.
  • Kim M; Division of Epidemiology, Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA 92093, USA.
  • Lee YS; NAFLD Research Center, University of California, San Diego, La Jolla, CA 92093, USA.
Sci Transl Med ; 16(764): eadi0284, 2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39259813
ABSTRACT
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Enfermedad del Hígado Graso no Alcohólico / Macrófagos del Hígado / Hígado / Activación de Macrófagos Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico / Enfermedad del Hígado Graso no Alcohólico / Macrófagos del Hígado / Hígado / Activación de Macrófagos Límite: Animals / Humans Idioma: En Revista: Sci Transl Med Asunto de la revista: CIENCIA / MEDICINA Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos