Hepatic nuclear factor erythroid 2 related factor 1 activity promotes host defense in endotoxemia and bacterial sepsis
Description
Background & Aims: Sepsis and endotoxemia cause mortality by inducing organ damage. The liver defends the host against such insults by mediating metabolic adaptations that promote tissue damage control. The control mechanisms underlying liver defenses are unclear but may require coordinated actions between cellular and systemic stress defense programs. Here, we investigated whether the cell stress defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) in hepatocytes play a role in host protection against endotoxemia and sepsis. Methods: We used mice injected with Escherichia coli derived lipopolysaccharide (endotoxemia), or live Escherichia coli (sepsis). Hepatic Nrf1 and Nrf2 activity was examined, and we also genetically altered their activity and examined the effect on survival, body temperature, cytokines and liver inflammation, liver gene and protein expression, and liver-related metabolism. Results: Hepatic Nrf1 and Nrf2 activity was reduced in endotoxemia and in sepsis, and deficiency for hepatic Nrf1, but not Nrf2, increased hypothermia and mortality. Conversely, increasing hepatic Nrf1 activity reduced hypothermia and improved survival. This effect was linked to hepatic very low-density lipoprotein (VLDL) secretion and circulating triglyceride metabolism. In mice with endotoxemia, hepatic Nrf1 deficiency reduced VLDL secretion, whereas increasing hepatic Nrf1 activity enhanced VLDL secretion. Also, administering the VLDL secretion inhibitor, lomitapide, diminished the protective effects of hepatic Nrf1 activity. Gene expression profiling indicate that Nrf1 may promote this effect by regulating stress defense programming. Conclusions: Mortality in endotoxemia and sepsis is exacerbated by impaired hepatic Nrf1 activity. Interventions that increase hepatic Nrf1 activity may promote VLDL-dependent liver defenses that protect against sepsis-associated hypothermia and mortality.