title: Fasting and refeeding differentially regulate NLRP3 inflammasome activation in human subjects.
abstract: BACKGROUND
  Activation of the NLRP3 inflammasome is associated with metabolic dysfunction, and intermittent fasting has been shown to improve clinical presentation of NLRP3 inflammasome-linked diseases. As mitochondrial perturbations, which function as a damage-associated molecular pattern, exacerbate NLRP3 inflammasome activation, we investigated whether fasting blunts inflammasome activation via sirtuin-mediated augmentation of mitochondrial integrity.
  
  
  METHODS
  We performed a clinical study of 19 healthy volunteers. Each subject underwent a 24-hour fast and then was fed a fixed-calorie meal. Blood was drawn during the fasted and fed states and analyzed for NRLP3 inflammasome activation. We enrolled an additional group of 8 healthy volunteers to assess the effects of the sirtuin activator, nicotinamide riboside, on NLRP3 inflammasome activation.
  
  
  RESULTS
  In the fasting/refeeding study, individuals showed less NLRP3 inflammasome activation in the fasted state compared with that in refed conditions. In a human macrophage line, depletion of the mitochondrial-enriched sirtuin deacetylase SIRT3 increased NLRP3 inflammasome activation in association with excessive mitochondrial ROS production. Furthermore, genetic and pharmacologic SIRT3 activation blunted NLRP3 activity in parallel with enhanced mitochondrial function in cultured cells and in leukocytes extracted from healthy volunteers and from refed individuals but not in those collected during fasting.
  
  
  CONCLUSIONS
  Together, our data indicate that nutrient levels regulate the NLRP3 inflammasome, in part through SIRT3-mediated mitochondrial homeostatic control. Moreover, these results suggest that deacetylase-dependent inflammasome attenuation may be amenable to targeting in human disease.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT02122575 and NCT00442195.
  
  
  BACKGROUND
  Division of Intramural Research, NHLBI of the NIH.
authors.forename: Javier
authors.initials: J
authors.lastname: Traba
authors.forename: Miriam
authors.initials: M
authors.lastname: Kwarteng-Siaw
authors.forename: Tracy C
authors.initials: TC
authors.lastname: Okoli
authors.forename: Jessica
authors.initials: J
authors.lastname: Li
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Huffstutler
authors.forename: Amanda
authors.initials: A
authors.lastname: Bray
authors.forename: Myron A
authors.initials: MA
authors.lastname: Waclawiw
authors.forename: Kim
authors.initials: K
authors.lastname: Han
authors.forename: Martin
authors.initials: M
authors.lastname: Pelletier
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Sauve
authors.forename: Richard M
authors.initials: RM
authors.lastname: Siegel
authors.forename: Michael N
authors.initials: MN
authors.lastname: Sack
mesh_terms: D000328:Adult; D002352:Carrier Proteins / Q000097:blood*; D004435:Eating; D005215:Fasting / Q000097:blood*; D005260:Female; D006801:Humans; D058847:Inflammasomes / Q000097:blood*; D008297:Male; D008928:Mitochondria / Q000378:metabolism*; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives; D011726:Pyridinium Compounds
chemical_list: D002352:Carrier Proteins; D058847:Inflammasomes; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human; D011726:Pyridinium Compounds; C018613:nicotinamide-beta-riboside; D009536:Niacinamide