Hepatic Nuclear Factor Erythroid 2 Related Factor 1 Activity Promotes Host Defense in Endotoxemia and Bacterial Sepsis.

BACKGROUND & AIMS: Sepsis and endotoxemia cause mortality by inducing organ dysfunction and damage. Liver defends against such insults by mediating metabolic adaptations that promote stress and damage control. The mechanisms underlying liver defenses may require coordinated actions between cellular and systemic stress-defense programming. Here, we investigated whether the stress-defending transcription factors nuclear factor erythroid 2 related factor-1 (Nrf1) and -2 (Nrf2) in hepatocytes protect against endotoxemia and sepsis. METHODS: We used mice injected with Escherichia coli-derived lipopolysaccharide (endotoxemia), or E coli (sepsis). Hepatic Nrf1 and Nrf2 activity was examined, and we also genetically altered their activity and examined corresponding effects 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 sepsis, and deficiency for hepatic Nrf1, but not Nrf2, promoted severe hypothermia and mortality. Conversely, increasing hepatic Nrf1 activity mitigated hypothermia and improved survival. These effects were linked to very-low-density lipoprotein (VLDL) secretion and triglyceride metabolism. In endotoxemia, hepatic Nrf1 deficiency reduced VLDL secretion, whereas increased hepatic Nrf1 activity enhanced VLDL secretion. Administering a VLDL secretion inhibitor, lomitapide, or inhibitor of circulating triglyceride hydrolysis, poloxamer 407, diminished protective effects of hepatic Nrf1 activity, whereas administering intralipid rescued the lomitapide-injected mice. Gene expression profiling indicates Nrf1 promotes this effect by regulating stress-defense programming. CONCLUSIONS: Mortality in endotoxemia and sepsis is exacerbated by impaired hepatic Nrf1 activity. Interventions increasing hepatic Nrf1 activity promote liver defenses that protect against sepsis-associated hypothermia and mortality.