Roles of SIRT1 in the acute and restorative phases following induction of inflammation.
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.
Department of Surgery, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, New Jersey 08903, USA.
Zhiyong
Z
Zhang
Stephen F
SF
Lowry
Leonard
L
Guarente
Beatrice
B
Haimovich
D000293:Adolescent; D000328:Adult; D000818:Animals; D005260:Female; D005294:Ferrochelatase / Q000737:chemistry; D006418:Heme / Q000737:chemistry; D006801:Humans; D007249:Inflammation; D008297:Male; D008670:Metals / Q000737:chemistry; D051379:Mice; D009154:Mutation; D011166:Porphyrins / Q000737:chemistry; D056564:Sirtuin 1 / Q000235:genetics* / Q000502:physiology*; D045725:Tetrapyrroles / Q000737:chemistry
D008670:Metals; D011166:Porphyrins; D045725:Tetrapyrroles; D006418:Heme; C447939:SIRT1 protein, human; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D005294:Ferrochelatase