Typically, serum levels of adiponectin, a potent anti-inflammatory cytokine, are reduced in NASH. “Immuno-metabolism” is an emerging field of research that investigates the co-regulation of metabolic and inflammatory pathways within immune cells. Chronic exposure of the immune system to particular nutrients can lead to metabolically triggered inflammation (meta-inflammation). In this context tissue resident macrophages play a pivotal role

in monitoring tissue function and restoring metabolic homeostasis. We explored how the intrinsic metabolic state of liver resident macrophages (Kupffer cells) change in NASH. Materials and Methods: Male C57BL/6 adiponectin knockout (ADN) and wild type mice were fed either normal chow (NC) or a high cholesterol CP-690550 cost (HC) diet for 12 weeks. At the end of this Paclitaxel mw period, serum and hepatic cholesterol were measured. Liver tissues were examined by haematoxylin and eosin (H&E), and by CD68 immunostaining. For in vitro analyses of immuno-metabolism, rat Kupffer cells were isolated and cultured in various concentrations of glucose and treated with LPS +/− adiponectin, and palmitate. qPCR and western blots were performed

to determine mRNA expression and to study changes in signaling molecules in liver tissue and kupffer cells. Results: When fed the high cholesterol diet, both genotypes had similar increases in average liver/total body weight ratio and reduced fat pad weight. Biochemistry and histology showed that KO mice fed the HC (ADN-HC) diet had significantly increased ALT levels, and elevated hepatic total (148 vs. 101 mg/dl, p < 0.05), crotamiton and free cholesterol (114 vs. 80 mg/dl, p < 0.05). ADN-HC livers had increased gene expression for TNFα (11-fold, p < 0.05) CD68 (6-fold, p < 0.05), IL-1β (1.4-fold, p < 0.05), CCL19 (6.0-fold, p < 0.01), liver pyruvate kinase (L-PK), (WT-HC 6.7-fold, ADN-HC 5-fold, p < 0.05), and 1.8-fold increase in expression of RelB by

western blot. In preliminary in vitro experiments, we find that treatment of Kupffer cells with LPS leads to increased glucose uptake. We detected incremental increases in LPS mediated activation of the NFkB pathway in macrophages cultured without glucose, low glucose (5 mM) and high glucose (25 mM) media. Adiponectin increased glucose uptake and adding adiponectin to the media increased NFkB activation, whereas palmitate reduced the uptake of glucose and suppressed activation of NFkB pathways. Conclusion: In vivo, adiponectin KO mice fed the high cholesterol diet had severe inflammation, with glycolytic pathway activation. Likewise, exposure to glucose modified the inflammatory status of Kupffer cells. These data suggest that Kupffer cell driven meta-inflammation plays an important role in hepatic immunometabolism and NASH pathogenesis.