Abstract
Endotoxin is a potent inducer of systemic inflammatory responses in human and rodents. Here, we show that in vivo endotoxin triggers a rapid and transient decline in ATP concentration in human peripheral blood leukocytes and murine peripheral blood leukocytes and liver, which is associated with a brief increase in expression of the autophagy indicator LC3-II. In both of these tissues, the ATP concentration reaches a nadir, and autophagy is induced between 2 and 4 h post-endotoxin infusion, and homeostasis is restored within 12 h. Mouse liver SIRT1 and AMP-activated protein kinase (AMPK) protein expression levels decline precipitously within 10 min and remain below detection levels for up to 12 h post-endotoxin administration. In marked contrast, the expression of HIF-1α is induced within 90 min and remains elevated for up to 12 h. The ATP recovery is delayed, and the increases in both HIF-1α expression and autophagy are prolonged in endotoxin-challenged SIRT1 liver knock-out mice. Resveratrol prevents the decline in ATP concentration and SIRT1 expression, as well as the increase in HIF-1α expression and autophagy in liver of endotoxin-challenged wild type mice but not in SIRT1 liver knock-out mice. These results provide novel insight into the state of both cellular bioenergetics and metabolic networks during the acute phase of systemic inflammation and suggest a role for SIRT1 in acute metabolic decline, as well as the restoration of metabolic homeostasis during an inflammatory challenge.
Highlights
Tabolism [1, 2]
We show that the cellular ATP levels, autophagy, as well as hypoxia-inducible transcription factor-1 (HIF-1)␣, silent information regulator T1 (SIRT1), and AMPK protein expression levels are all coordinately dysregulated in human and mice leukocytes and in mice liver as early as 1–2 h after an in vivo endotoxin challenge
In Vivo Endotoxin Triggers a Transient Decrease in Cellular ATP Concentration and a Parallel Increase in Autophagy in Peripheral Blood Leukocytes and Liver Tissue—Endotoxin triggers transient changes in expression of genes associated with the mitochondrial oxidative phosphorylation activity in human PBL [50]. To determine whether these changes in mitochondrial gene expression reflect changes in cellular bioenergetics, we examined the ATP concentration in PBL obtained from human subjects at multiple time points before and after an in vivo endotoxin challenge
Summary
Tabolism [1, 2]. Among the abundant data that support its metabolic function [3, 4], the observations that SIRT1-null mice are metabolically inefficient as compared with normal mice, and that their liver mitochondria have a lower capacity to produce ATP, are significant [5]. We show that the cellular ATP levels, autophagy, as well as HIF-1␣, SIRT1, and AMPK protein expression levels are all coordinately dysregulated in human and mice leukocytes and in mice liver as early as 1–2 h after an in vivo endotoxin challenge.
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