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Macrophage-specific PHGDH protects against MAFLD by suppressing TAK1
Penghui Hu1, Xiao Shan2, Hongyuan Dong3
1Department of Critical Care Medicine, Tianjin Medical University General Hospital, Tianjin 300052, China; Tianjin Institute of Immunology, State Key Laboratory of Experimental Hematology, Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), Department of Immunology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
Abstract:
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive disease with only one approved treatment currently available. Hepatic phosphoglycerate dehydrogenase (PHGDH), the rate-limiting enzyme of the serine biosynthesis pathway, regulates MAFLD development. However, the role of macrophage PHGDH in MAFLD progression remains unclear. Here, we demonstrate that the lipotoxicity inducer palmitic acid (PA) significantly increases macrophage PHGDH expression and that PHGDH deficiency in macrophages promotes PA-induced inflammatory responses. Myeloid-specific PHGDH deficiency exacerbates MAFLD in mice. Mechanistically, tetrameric PHGDH binds to transforming growth factor-β-activated kinase 1 (TAK1) to inhibit its interaction with TAK1 binding protein 1 (TAB1), sequentially suppressing the activation of TAK1 and downstream NF-κB and MAPK signaling. Inhibition of TAK1 activation slows the development of metabolic dysfunction-associated steatohepatitis (MASH) caused by myeloid PHGDH knockout. Importantly, adeno-associated virus-mediated PHGDH overexpression in liver macrophages alleviates MAFLD in mice. Collectively, these results identify macrophage PHGDH as a promising therapeutic agent for MAFLD.
Insights
Macrophage PHGDH protects against metabolic dysfunction-associated fatty liver disease (MAFLD). PHGDH deficiency worsens MAFLD, while its overexpression alleviates the condition, suggesting PHGDH as a therapeutic target.
Area of Science:
- Hepatology
- Immunology
- Metabolic Diseases
Background:
- Metabolic dysfunction-associated fatty liver disease (MAFLD) is a progressive condition with limited treatment options.
- Hepatic phosphoglycerate dehydrogenase (PHGDH), key to serine biosynthesis, influences MAFLD, but its role in macrophages is unknown.
Purpose of the Study:
- To investigate the role of macrophage PHGDH in the development and progression of MAFLD.
- To explore PHGDH as a potential therapeutic target for MAFLD.
Main Methods:
- Palmitic acid (PA) treatment to induce lipotoxicity in macrophages.
- Generation of myeloid-specific PHGDH knockout mice.
- Adeno-associated virus (AAV)-mediated PHGDH overexpression in liver macrophages.
- Analysis of inflammatory signaling pathways (TAK1, NF-κB, MAPK).
Main Results:
- Palmitic acid increased macrophage PHGDH expression.
- PHGDH deficiency in macrophages exacerbated PA-induced inflammation and MAFLD progression in mice.
- PHGDH interacts with TAK1, inhibiting TAK1/TAB1 complex formation and downstream signaling.
- Macrophage PHGDH overexpression ameliorated MAFLD in mice.
Conclusions:
- Macrophage PHGDH plays a protective role in MAFLD pathogenesis.
- Targeting macrophage PHGDH may offer a novel therapeutic strategy for MAFLD and metabolic dysfunction-associated steatohepatitis (MASH).
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