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Fig. 1
Activation of two NF-κB signaling pathways. Activation of NF-κB by immune stimuli involves canonical and noncanonical pathways, which are based on degradation of IκB or processing of p100, respectively. The canonical pathway is stimulated by diverse cellular stimuli, such as antigens and cytokines, and is dependent on the trimeric IKK complex. The noncanonical pathway responds to a subset of TNF family members, including BAFF and CD40L, and requires IKKα but not IKKγ or IKKβ. BAFF; B cell activating factor.
Fig. 2
Proposed model of metabolic and inflammatory signaling and sensing pathways in adipocytes, macrophages and hepatocytes. Adipocytes secrete factors that attract monocytes and lead to differentiation of monocytes into resident macrophages. Together, adipocytes and macrophages interact, increasing circulating proinflammatory cytokines, promoting a chronic, systemic inflammatory response that adversely affects metabolic function and leads to diabetes. Inflammatory pathways can be initiated by extracellular mediators such as cytokines and lipids or by intracellular stresses such as ER stress or excess ROS production by mitochondria. Signals from all of these mediators converge on inflammatory signaling pathways, including IKK. Key initiating events in the liver are 1) hepatic activation of serine/threonine kinases (IKK), which presumably caused insulin resistance at the IRS-1/2 level, and 2) the activation of the IKK/IκBα/NF-κB pathway (via PKC, ROS, or other mechanisms), leading to expression and secretion of inflammatory cytokines (TNFα, IL-1, IL-6, and MCP-1). ICAM, intercellular adhesion molecule; IL-6, interleukin-6; IR, insulin receptor; IRS, insulin receptor substrate; MCP-1, monocyte chemoattractant protein-1; M-CSF, macrophage colony-stimulating factor; MIF, macrophage migration inhibitory factor MIP, macrophage inflammatory protein; PAI-1, plasminogen activator inhibitor-1; TNF-α, tumor necrosis factor-α.
Fig. 3
Schematic representation of atherogenesis. Indicated are the different cell types involved and the different steps in the atherosclerotic process potentially affected by NF-B activation. (1)Initiation of atherosclerosis is characterized by the formation of modified LDL (mLDL), followed by the subsequent activation of endothelial cells and secretion of chemokines. On migration through the endothelial layer, the monocytes differentiate into macrophages and scavenge the modified LDL from the vessel wall, resulting in (2) foam cell formation. Persistent hypercholesterolemia leads to intracellular accumulation of cholesteryl esters and eventually apoptosis and release of proinflammatory oxidized lipid derivatives into the plaque, further exacerbating the (3)inflammatory responses. (4), (5) Later stages involve the formation of a fibrotic cap through proliferation and migration of smooth muscle cells and cell death resulting in a necrotic core. SR indicates scavenger receptor. Modified from reference[88].
Table 1
Comparison of NF-κB tissue-specific knockout or transgenic mouse models
The different mouse models have various age- and diet-dependent responses; therefore, for simplicity, the descriptions are for the adult phenotype on a described diet and compared to wild-type on the same diet.
HFD, high fat diet; FFA, free fatty acid; S, similar to control; n/c, no comment.
*plasma.
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