Maternal Western-style Diet Promotes Immune Tolerance and Liver Sinusoidal Endothelial Cell Dysfunction in Nonhuman...

Maternal Western-style diet (mWSD) consumption during pregnancy and lactation is associated with developmental programming of metabolic dysfunction-associated steatotic liver disease (MASLD) in offspring. To understand the roles of immune and endothelial cells, we used single-cell RNA-sequencing of liver non-parenchymal cells from 3-year-old juvenile nonhuman primates exposed to mWSD during their gestation through weaning, followed by control diet consumption after weaning. We identified unique clusters of macrophages in mWSD-exposed juvenile livers with non-reparative, pro-fibrotic phenotypes characterized by predicted inactivation of NF-κB, decreased oxidative phosphorylation, and gene expression facilitating hepatic stellate cell-macrophage interactions. Kupffer cell and dendritic cell (DC) numbers were decreased by mWSD exposure, with inactivation of inflammatory and antigen presentation pathways in DCs, supporting DC immaturity. B cells increased in mWSD-exposed offspring, with RNA showing reduced inflammation and impaired differentiation, while T cells had RNA profiles consistent with apoptosis and reduced inflammatory function. mWSD exposure increased clusters of liver sinusoidal endothelial cells (LSECs), with activation of inflammation and proliferation pathways but decreased immune cell communication. Immunocytochemistry and RNAscope identified increased association of LSECs and immune cells in periportal regions. In summary, mWSD exposure during gestation and lactation selectively modulated LSEC-immune cell interactions consistent with immune tolerant B and T cells and fibrogenic pathways together with decreased pro-resolving macrophages in juvenile offspring. We conclude that mWSD exposure establishes an immune-tolerant environment in offspring liver, marked by a durable, pro-fibrotic microenvironment that resists postnatal dietary correction.