Title: Roles of SIRT1 in the acute and restorative phases following induction of inflammation.

Authors: Zhang, Zhiyong; Lowry, Stephen F; Guarente, Leonard; Haimovich, Beatrice

Published In J Biol Chem, (2010 Dec 31)

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.

PubMed ID: 20966076

MeSH Terms: Adolescent; Adult; Animals; Female; Ferrochelatase/chemistry; Heme/chemistry; Humans; Inflammation; Male; Metals/chemistry; Mice; Mutation; Porphyrins/chemistry; Sirtuin 1/genetics*; Sirtuin 1/physiology*; Tetrapyrroles/chemistry