Moreover, KC activation and defective phagocytosis, as reported here, have
been observed in the induction and potentiation of NAFLD.18, 21 Previous reports have suggested that steatosis may disrupt sinusoid microcirculation and hepatocellular clearance of microbial antigens, all of which activate KCs.22 KCs account for 80%-90% of the total fixed-tissue whole body macrophage population,23 and we found them to be present in greater number in OffCon-OD and OffOb-OD. Others have made similar observations in a rat model of NASH, where KCs are recruited and activated after exposure to a high-fat diet.24 KCs possess the ability of functional polarisation to release proinflammatory (M1 phenotype) or anti-inflammatory (M2 phenotype) cytokines.13 Such M1 phenotypic cytokines include IL-6, IL-12, IL-18, and TNF-α, all of which we report here find more to be up-regulated in OffOb-OD. TNF-α, an adipokine, is implicated BTK inhibitor libraries in NAFLD pathogenesis through its promotion of IR, which, in turn, promotes hepatosteatosis, and perturbation of electron transport chain redox reactions to induce increased ROS production.11 TNF-α antagonism has been shown to improve histological features of NAFLD in the ob/ob mouse model, highlighting its importance in NAFLD pathogenesis.25 These M1 phenotypic cytokines are also up-regulated in response to increased oxidation of
free fatty acids.26 KCs are also able to directly generate ROS by the nicotinamide adenine dinucleotide 上海皓元 phosphate oxidase-dependent and the xanthine oxidase-dependent pathways.27 KC-derived ROS is well documented in alcoholic liver disease,21 which bears histological resemblance to NAFLD. As such, KC-mediated ROS has been implicated in NAFLD pathogenesis. Here, we report novel, direct evidence of elevated ROS production by KC, rising proportionately with increased KC numbers in the offspring
of the obese dams challenged with a postnatal obesogenic diet. These findings are in keeping with previous reports of gross hepatic ROS production mediating NAFLD in genetically modified rats.28 Here, we report reduced phagocytic function in the context of increased KC number. These findings are supported by previous studies in rodent models of obesity and NAFLD and in patients with biopsy-proven NASH.29, 30 Impaired KC phagocytosis evokes overproduction and sensitivity to key inflammatory mediators, enhancing hepatic inflammation and propagating injury in NAFLD. Moreover, reduced clearance of dead cells and LPS generate a hyperendotoxaemic state, potentiating proinflammatory pathways.21 NKT cells are presently thought to modulate inflammatory responses by achieving a balance between T-helper cells (Th)-1 and Th-2 polarization states within the liver. NKT cell depletion has been associated with worsened NAFLD phenotypes not only in the present study, but also in ob/ob leptin-deficient mice,14 models of diet-induced NAFLD,31 and human biopsied NASH livers.