Browsing by Author "HUANG, YIMAO"

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    The role of macrophage inflammation and adipocyte secretion in obesity and diabetes
    (2022-04) HUANG, YIMAO
    Obesity-linked diabetes is associated with the accumulation of pro-inflammatorymacrophages into adipose tissue leading to inflammasome activation and pyroptotic secretion of IL-1b and IL-18. Targeting fatty acid binding protein 4 (FABP4) uncouples obesity from inflammation, attenuates characteristics of type II diabetes, and is mechanistically linked to the cellular accumulation of monounsaturated fatty acids in macrophages. We show that pharmacologic inhibition or genetic deletion of FABP4 activates SIRT1 and deacetylates its downstream targets p53 and STAT3. Pharmacologic inhibition of fatty acid synthase or stearoyl CoA desaturase inhibits, whereas exogenous addition of C16:1 or C18:1 but not their saturated acyl chain counterparts activates SIRT1 and p53/STAT3 signaling and IL-1b/IL-18 release. Expression of the p53 target gene ASC required for assembly of the NLRP3 inflammasome is downregulated in FABP4 null mice and macrophage cell lines leading to loss of pro-caspase 1 activation and pyroptosis. Concomitant with the loss of ASC expression in FABP4-/- macrophages, inflammasome activation, gasdermin D processing, and functional activation of pyroptosis are all diminished in FABP4 null macrophages. Still, they can be rescued by silencing SIRT1 or exogenous expression of ASC. These results reveal a novel lipid-regulated pathway linking to SIRT1-p53-ASC signaling and activation of inflammasome action and pyroptosis.