Strategies to recover liver regeneration after partial hepatectomy in obese mice

Abstract

Liver regeneration is vital for recovering liver function after surgical resection or transplantation. Using a mouse model for HpX, we were capable of identifying the role of different subsets of hepatic macrophages during liver regeneration. Specifically, we identified that KC, and not moM, are the key necessary cell type in the production of cytokines and growth factors to promote liver regeneration. KC depletion with clodronate liposomes led to decreased liver regeneration and increased mortality in mice after operation. CCR2^-/- mice, where monocytes are not capable of migrating into tissue, and have no moM, showed minimal impairment in liver regeneration, compared to WT. <br /> Obesity causes severe difficulties to liver regeneration after HpX in patients and animals. HFD-induced obesity led to a disruption in KC function and numbers, replacing them with pro-inflammatory moM. Using the Microfetti mouse model we found that KC from obese mice have impaired clonal expansion after HpX. Transcriptomic and metabolic analyses revealed that KC from obese mice exhibit diminished cytokine and growth factor production as well as impaired reactive oxygen species generation. <br /> Obesity leads to gut dysbiosis and microbial translocation. These led to increased levels of pathogenic bacteria in the liver, as identified by 16S rRNA sequencing. Type I interferons emerged as a key negative regulator of liver regeneration in our transcriptomic data set. IFNAR1 mediated sensing of IFN I caused an impaired proliferation capacity in KC and led to increased recruitment of moM. Targeting IFNAR1 with a blocking antibody was sufficient to rescue liver regeneration in obese mice after HpX. IFNAR blockade did not fully restore KC numbers. Bulk RNA sequencing of KC after IFNAR blockade showed an increase in production of the growth factor HB-EGF as well as increasing OXPHOS. IFNAR blockade also contributed to reduce amounts of IL-6 production by KC and its concentration in the plasma of mice. <br /> In conclusion, this study highlights the crucial role of KC in liver regeneration, the detrimental effects of obesity on KC function, and the potential of the IFNAR signaling pathway as a therapeutic target to improve liver regeneration in obese patients.