Impaired liver regeneration in obesity is driven by IFNAR signaling in Kupffer cells

Liver regeneration is essential for restoring hepatic function after surgical resection or transplantation. Obesity and metabolic-driven chronic liver inflammation (metaflammation) are recognized as major inhibitors of liver regrowth. In a murine model of partial hepatectomy (HpX), we identified Kupffer cells (KCs)—rather than monocyte-derived macrophages—as the key mediators of liver regeneration. Transcriptomic and proteomic analyses of KCs during the early phase of regeneration revealed that in lean mice, resident KCs commit to tissue regeneration by suppressing innate and IFNAR-associated transcriptional programs to meet the metabolic demands for the activate liver regeneration programs. Conversely, KCs from obese mice exhibited a pronounced interferon-alpha/beta receptor (IFNAR) and innate immunity-associated signature, coupled with impaired clonal expansion and reduced metabolic fitness. Obesity-induced gut dysbiosis and microbial translocation exacerbated hepatic inflammation and inhibited regeneration by inducing type I interferon (IFN-I) signaling in KCs. Systemic inhibition or genetic deletion of IFNAR in KCs restored their proliferative capacity and metabolic fitness, leading to liver regeneration in obese mice comparable to that in lean mice. This study highlights the critical role of KCs in liver regeneration, the deleterious effects of obesity-driven chronic IFN-I signaling, and the potential of targeting this pathway to enhance liver regeneration in obese individuals.

 

Scroll to top

Publikationsverlauf

Artikel online veröffentlicht:
20. Januar 2025