To investigate the role of senescent macrophages in liver fibrosis and elucidate the underlying mechanisms.
Approach:
Animal Model: Liver fibrosis was induced in young and middle-aged mice using carbon tetrachloride (CCl4) injections.
In Vitro Studies: A senescent macrophage model was established in RAW264.7 cells, and conditioned medium was transferred to LX-2 cells to assess hepatic stellate cell activation.
Transcriptome Analysis: Transcriptome sequencing of senescent RAW264.7 cells was performed to identify metabolic reprogramming mechanisms.
Protein Stability Assays: FASN protein stability was examined using cycloheximide chase assays and degradation pathways were explored.
Key Findings:
Middle-aged mice exhibited more severe hepatic collagen deposition and fibrosis compared to young mice.
Senescent macrophages showed upregulated SASP components, including pro-inflammatory cytokines and chemokines, and promoted LX-2 cell activation.
Transcriptome sequencing revealed downregulation of fatty acid β-oxidation genes and upregulation of fatty acid synthesis genes.
FASN protein underwent dual degradation via ubiquitin-proteasome and autophagy pathways.
Pharmacological inhibition of FASN reduced the DNA damage response in senescent macrophages.
Interpretation:
Macrophages in middle-aged fibrotic livers exhibit cellular senescence, with FASN-mediated lipid metabolic disorder contributing to liver fibrosis progression.
Limitations:
The study primarily focuses on mouse models, which may not fully replicate human liver fibrosis.
Further research is needed to explore the clinical relevance of findings in human subjects.
Conclusion:
Senescent macrophages enhance fatty acid synthesis, leading to lipid accumulation and promoting hepatic stellate cell activation, driving liver fibrosis.
