Mus musculus Raw sequence reads. Mus musculus

Endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) are common findings in obesity-induced non-alcoholic fatty liver disease (NAFLD). The pro-resolving mediator maresin 1 (MaR1) is known to preserve tissue homeostasis by dampening inflammation and expediting timely resolution. In the current study, we explored whether MaR1 is able to protect liver cells from hypoxia and lipotoxic-induced ER stress and injury. Obese mice with NAFLD showed a remarkable up-regulation of hypoxia (i.e. CA9 and HIF-1α) and ER stress (peif2α, pJNK, ATF3 and BiP) markers. Primary hepatocytes cultured under hypoxic conditions showed increased ER stress (pIRE1α, peif2α, CHOP and ATF3) and altered autophagy (LC3-II, ATG7 and p62), abnormalities that were prevented by MaR1. Notably, MaR1 protected hepatocytes from apoptotic cell death as revealed by a significant reduction in caspase 3/7 activity. The cytoprotective actions of MaR1 were also seen in primary hepatocytes cultured under palmitate-induced lipotoxic conditions, in which MaR1 activated the pro-survival mechanisms and prevented excessive up-regulation of pro-apoptotic pathways. Moreover, MaR1 rescued the palmitate-impaired phagocytic capacity of Kupffer cells. In precision-cut liver slices, an ex vivo model that mantains the original hepatic architecture and the original liver resident cells, MaR1 prevented lipotoxic-triggered ER stress and hypoxia-induced TNFα and IL-1β up-regulation. Finally, MaR1 actions on liver cells were associated with specific miRNA signatures depending on the ER stressor. The present study describes the ability of the pro-resolving lipid mediator MaR1 to oppose ER stress in hepatocytes under conditions that promote the progression of obesity-induced NAFLD.