Endothelial NO/cGMP/VASP Signaling Attenuates Kupffer Cell Activation and Hepatic Insulin Resistance Induced by High-Fat Feeding

  1. Francis Kim1,2
  1. 1Department of Medicine, University of Washington, Seattle, Washington
  2. 2Diabetes and Obesity Center of Excellence, University of Washington, Seattle, Washington
  3. 3Department of Surgery, University of Washington, Seattle, Washington
  1. Corresponding author: Francis Kim, fkim{at}


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.

RESEARCH DESIGN AND 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.

  • Received February 23, 2011.
  • Accepted August 2, 2011.

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  1. Diabetes vol. 60 no. 11 2792-2801
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