Periportal hepatocytes secret SAA1 to recruit MoKCs and interactions through CADM1 signaling to promote MASLD

In non-alcoholic steatohepatitis, there is a compensatory increase in monocyte-derived Kupffer cells (MoKCs) due to the loss of resident Kupffer cells. However, the mechanisms behind MoKCs recruitment and their impact on steatohepatitis development remain unclear. We aimed to elucidate the contribution of continuously recruited MoKCs and the interaction between MoKCs and other cells in macrophage-mediated metabolic dysfunction associated steatotic liver disease (MASLD) to disease exacerbation.

We utilized snRNA-seq analysis parallel to characterize the transcriptomes of hepatocytes and non-parenchymal cells (NPCs) in the MASLD progression of steatosis to fibrosis livers in mice and humans, integrating multi-omics analyses among the program. We used spatial transcriptome analysis to discover key functional compartments to recruit MoKCs in MASLD progression. Further performed the critical cytokine validation by genome-wide association analysis combine with genetic risk scores construction in 5,936 individuals. The signal that recruited MoKCs damaging hepatocytes was explored by cell-cell communication analysis and co-culture system.

We confirmed through difference cytokine screening and spatial transcriptome that serum amyloid A1 (SAA1) is significantly involved in the pathogenesis of MASLD as evidenced by periportal hepatocytes (PPHs) recruiting MoKCs through the secretion of SAA1. The polygenetic risk score also indicated SAA1 significantly increased MASLD risk in UK Biobank cohort. The recruited MoKCs can in turn disrupt liver microenvironment homeostasis through abnormal cell-cell interactions with hepatocytes, endothelial cells (ECs) and hepatic stellate cells (HSCs). Of these, the recruited MoKCs damaging hepatocytes via CADM1 signal was validated through co-culture system.

These findings enhance our comprehension of MoKCs recruitment and turnover in humans and mice, emphasizing their critical role in the multiple-hit injury process during MASLD development.