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Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding.

Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, Clowes AW, Morton GJ, Schwartz MW, Kim F - Diabetes (2011)

Bottom Line: 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.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.Our findings also identify the NO/VASP pathway as a novel potential target for the treatment of obesity-associated liver insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.

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.

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.

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Hepatic inflammation and insulin resistance in eNos−/− mice. eNos−/− mice and littermate control mice were fed a low-fat (LF) or a high-fat (HF) diet for 4 weeks from age 8 weeks. A and B: Liver lysates were analyzed for IκB-α phosphorylation by Western blot and IL-6 mRNA expression by RT-PCR (n = 7). *P < 0.05. C: Inflammatory markers from isolated Kupffer cells by RT-PCR (n = 5). *P < 0.05. D: Hepatic insulin (Ins) signaling at the level of Akt phosphorylation (n = 5). *P < 0.05. E: Hepatic triglyceride (TG) content (n = 7). *P < 0.05. Veh, vehicle; WT, wild type. IB, immunoblot; kD, kilodalton.
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Figure 2: Hepatic inflammation and insulin resistance in eNos−/− mice. eNos−/− mice and littermate control mice were fed a low-fat (LF) or a high-fat (HF) diet for 4 weeks from age 8 weeks. A and B: Liver lysates were analyzed for IκB-α phosphorylation by Western blot and IL-6 mRNA expression by RT-PCR (n = 7). *P < 0.05. C: Inflammatory markers from isolated Kupffer cells by RT-PCR (n = 5). *P < 0.05. D: Hepatic insulin (Ins) signaling at the level of Akt phosphorylation (n = 5). *P < 0.05. E: Hepatic triglyceride (TG) content (n = 7). *P < 0.05. Veh, vehicle; WT, wild type. IB, immunoblot; kD, kilodalton.

Mentions: To test whether genetic absence of vascular eNOS reproduces the effect of high-fat feeding to induce liver inflammation and insulin resistance, we studied adult male eNos−/− mice and wild-type control mice fed either a low-fat or high-fat diet for a relatively short period (4 weeks). As expected, liver IκB-α phosphorylation and IL-6 mRNA expression in liver tissues of wild-type mice were not increased after only 4 weeks on either diet, whereas both markers of NF-κB activation were significantly increased in the liver of eNos−/− mice, regardless of the fat content of their diet (Fig. 2A and B). Similarly, inflammatory activation was observed in Kupffer cells in the eNos−/− mice, and mRNA expression encoding TNF-α, iNOS, IL-6, and CD11c were each increased significantly (Fig. 2C).


Endothelial NO/cGMP/VASP signaling attenuates Kupffer cell activation and hepatic insulin resistance induced by high-fat feeding.

Tateya S, Rizzo NO, Handa P, Cheng AM, Morgan-Stevenson V, Daum G, Clowes AW, Morton GJ, Schwartz MW, Kim F - Diabetes (2011)

Hepatic inflammation and insulin resistance in eNos−/− mice. eNos−/− mice and littermate control mice were fed a low-fat (LF) or a high-fat (HF) diet for 4 weeks from age 8 weeks. A and B: Liver lysates were analyzed for IκB-α phosphorylation by Western blot and IL-6 mRNA expression by RT-PCR (n = 7). *P < 0.05. C: Inflammatory markers from isolated Kupffer cells by RT-PCR (n = 5). *P < 0.05. D: Hepatic insulin (Ins) signaling at the level of Akt phosphorylation (n = 5). *P < 0.05. E: Hepatic triglyceride (TG) content (n = 7). *P < 0.05. Veh, vehicle; WT, wild type. IB, immunoblot; kD, kilodalton.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3198085&req=5

Figure 2: Hepatic inflammation and insulin resistance in eNos−/− mice. eNos−/− mice and littermate control mice were fed a low-fat (LF) or a high-fat (HF) diet for 4 weeks from age 8 weeks. A and B: Liver lysates were analyzed for IκB-α phosphorylation by Western blot and IL-6 mRNA expression by RT-PCR (n = 7). *P < 0.05. C: Inflammatory markers from isolated Kupffer cells by RT-PCR (n = 5). *P < 0.05. D: Hepatic insulin (Ins) signaling at the level of Akt phosphorylation (n = 5). *P < 0.05. E: Hepatic triglyceride (TG) content (n = 7). *P < 0.05. Veh, vehicle; WT, wild type. IB, immunoblot; kD, kilodalton.
Mentions: To test whether genetic absence of vascular eNOS reproduces the effect of high-fat feeding to induce liver inflammation and insulin resistance, we studied adult male eNos−/− mice and wild-type control mice fed either a low-fat or high-fat diet for a relatively short period (4 weeks). As expected, liver IκB-α phosphorylation and IL-6 mRNA expression in liver tissues of wild-type mice were not increased after only 4 weeks on either diet, whereas both markers of NF-κB activation were significantly increased in the liver of eNos−/− mice, regardless of the fat content of their diet (Fig. 2A and B). Similarly, inflammatory activation was observed in Kupffer cells in the eNos−/− mice, and mRNA expression encoding TNF-α, iNOS, IL-6, and CD11c were each increased significantly (Fig. 2C).

Bottom Line: 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.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.Our findings also identify the NO/VASP pathway as a novel potential target for the treatment of obesity-associated liver insulin resistance.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, University of Washington, Seattle, Washington, USA.

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.

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.

Show MeSH
Related in: MedlinePlus