title: Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding.
abstract: OBJECTIVE
  Proinflammatory activation of Kupffer cells is implicated in the effect of high-fat feeding to cause liver insulin resistance. We sought to determine whether reduced endothelial nitric oxide (NO) signaling contributes to the effect of high-fat feeding to increase hepatic inflammatory signaling and if so, whether this effect 1) involves activation of Kupffer cells and 2) is ameliorated by increased NO signaling.
  
  
  METHODS
  Effect of NO/cGMP signaling on hepatic inflammation and on isolated Kupffer cells was examined in C57BL/6 mice, eNos(-/-) mice, and Vasp(-/-) mice fed a low-fat or high-fat diet.
  
  
  RESULTS
  We show that high-fat feeding induces proinflammatory activation of Kupffer cells in wild-type mice coincident with reduced liver endothelial nitric oxide synthase activity and NO content while, conversely, enhancement of signaling downstream of endogenous NO by phosphodiesterase-5 inhibition protects against high fat-induced inflammation in Kupffer cells. Furthermore, proinflammatory activation of Kupffer cells is evident in eNos(-/-) mice even on a low-fat diet. Targeted deletion of vasodilator-stimulated phosphoprotein (VASP), a key downstream target of endothelially derived NO, similarly predisposes to hepatic and Kupffer cell inflammation and abrogates the protective effect of NO signaling in both macrophages and hepatocytes studied in a cell culture model.
  
  
  CONCLUSIONS
  These results collectively imply a physiological role for endothelial NO to limit obesity-associated inflammation and insulin resistance in hepatocytes and support a model in which Kupffer cell activation during high-fat feeding is dependent on reduced NO signaling. Our findings also identify the NO/VASP pathway as a novel potential target for the treatment of obesity-associated liver insulin resistance.
authors.affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.
authors.forename: Sanshiro
authors.initials: S
authors.lastname: Tateya
authors.forename: Norma O
authors.initials: NO
authors.lastname: Rizzo
authors.forename: Priya
authors.initials: P
authors.lastname: Handa
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Cheng
authors.forename: Vicki
authors.initials: V
authors.lastname: Morgan-Stevenson
authors.forename: Guenter
authors.initials: G
authors.lastname: Daum
authors.forename: Alexander W
authors.initials: AW
authors.lastname: Clowes
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects; D006505:Hepatitis / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D007333:Insulin Resistance; D007728:Kupffer Cells / Q000276:immunology / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics*; D009765:Obesity / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000098662:Vasodilator-Stimulated Phosphoprotein
chemical_list: D015815:Cell Adhesion Molecules; D016207:Cytokines; D004041:Dietary Fats; D008840:Microfilament Proteins; D058986:Phosphodiesterase 5 Inhibitors; D010750:Phosphoproteins; D000098662:Vasodilator-Stimulated Phosphoprotein; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; C496315:Nos3 protein, mouse; D006152:Cyclic GMP