Background/Purpose: High dietary content of fructose (in table sugar, sweetened sodas, energy beverages, and fruit juices) is a substantial risk factor for both hyperuricemia and developing gout. Fructose is well recognized to elevate serum uric acid via increased hepatic uric acid production through ATP consumption needed to metabolize fructose. Specifically, fructose metabolism in multiple cell types can lead to ATP depletion, and generation of AMP, and also of uric acid through xanthine oxidase (XO). The objective of this study was to test the hypothesis that fructose is pro-inflammatory in vitro in human monocyte-macrophage lineage cells, which play a major role in initiating and regulating the gout inflammation cascade. In doing so, we examined the roles of fructose stimulated uric acid generation. Soluble uric acid decreases hepatocyte activity of AMP-activated protein kinase (AMPK), a constitutive master inhibitor of inflammatory responses to urate crystals. AMPK tissue activity is decreased in obesity and diabetes.

Methods: Human monocytic THP-1 cells were cultured in RPMI media (1% FCS) containing 5 mM glucose for 24 hours. Fructose (5 or 15 mM) was then added to the media, and cells were cultured for additional 48 hours. For controls, glucose (2, 5 or 15 mM) was used instead of fructose. In some cases, febuxostat (xanthine oxidease inhibitor, 1 µM)) was added 30 min before addition of fructose. To determine the effect on fructose on inflammatory potential of THP-1 cells, twenty-four hours after addition of fructose, the cells were treated with LPS (1µg/ml) for another 24 hours. Expression of total AMPKα, Thr172 phosphorylated AMPKα indicative of AMPK activation, andexpression of AMP deaminase 1 (AMPD1) were examined by Western blot analysis. Inflammatory cytokine and chemokine IL-1β and CXCL8, respectively, were measured by ELISA.

Results: Decreased phosphorylation of AMPKα, correlated with increased expression of AMPD1, were observed in THP-1 cells in response to fructose, but not glucose, at 5 and 15 mM concentrations. In addition, these effects were inhibited by febuxostat, suggesting dependence of endogenous uric acid generation. In comparison, fructose at 2 mM concentration had no effect on phosphorylation of AMPKa and expression of AMPD1. Moreover, inflammatory potential of THP-1 cells was enhanced by fructose, evidenced by significantly increased LPS-induced expression of IL-1β and CXCL8 (by ~30% and 20%, respectively).

Conclusion: Excessive dietary fructose can increase peripheral monocyte inflammatory potential by reducing AMPK activity, in association with endogenously cell-generated uric acid. These observations may contribute to the marked increase in risk of developing gouty arthritis in those with high dietary fructose.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/fructose-amplifies-inflammatory-potential-in-human-monocytic-cells-via-reduction-of-amp-activated-protein-kinase-activity/