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Macrophages Atp6v0d2 regulates XBP1-mediated cholesterol metabolism to suppress metabolic dysfunction-associated

Ziyi Wang1, Xuejiao Chen2, Jie Li1

  • 1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China; Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, Nanjing, China; NHC Key Laboratory of Hepatobiliary Cancers, (Nanjing Medical University), Nanjing, China.

International Immunopharmacology
|June 17, 2025
PubMed
Abstract

Insights

Activating Atp6v0d2 in myeloid cells protects against metabolic dysfunction-associated steatohepatitis (MASH). This gene

Area of Science:

  • Immunology
  • Hepatology
  • Molecular Biology

Background:

  • Metabolic dysfunction-associated steatohepatitis (MASH) involves myeloid-derived macrophages (MDMs).
  • Atp6v0d2, a macrophage-specific gene linked to Trem2, is upregulated in MASH livers.
  • The precise role of Atp6v0d2 in MASH pathogenesis requires elucidation.

Purpose of the Study:

  • To investigate the functional significance of Atp6v0d2 in MDMs during MASH.
  • To explore Atp6v0d2 as a potential therapeutic target for MASH.

Main Methods:

  • Generated myeloid-specific Atp6v0d2 knockout mice (Atp6v0d2Δmye) and global knockout mice (Atp6v0d2-/-).
  • Utilized myeloid Trem2 knockout mice (Trem2Δmye) and Trem2 reporter mice.
  • Studied these models in diet-induced obesity (DIO) mouse models (GAN and CDAHFD).

Main Results:

  • Atp6v0d2 deficiency in MDMs exacerbated hepatic steatosis and fibrosis in DIO mice.
  • Upregulation of Atp6v0d2 conferred protection against MASH progression.
  • Atp6v0d2 deficiency induced endoplasmic reticulum stress, impaired anti-inflammatory macrophage phenotype, increased apoptosis, and reduced cholesterol efflux, disrupting efferocytosis and leading to hepatocyte accumulation.
  • Administration of TAK-242, inducing Atp6v0d2 overexpression, ameliorated MASH pathology.

Conclusions:

  • Myeloid-specific Atp6v0d2 plays a critical role in maintaining hepatic lipid homeostasis and suppressing MASH.
  • Targeted activation of Atp6v0d2 represents a promising therapeutic strategy for MASH.
Keywords:
Atp6v0d2CholesterolEfferocytosisMASHTrem2Xbp1

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