pISSN 1976-2283
eISSN 2005-1212

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Fig. 1. Excess lipid accumulation activates inflammatory pathways and induces insulin resistance. Extracellular free fatty acids (FFA) activate toll-like receptors (TLR), causing downstream activation of c-Jun N-terminal kinase (JNK) and IκB kinase (IKK) complex (composed of IKKα, IKKβ and NF-κB essential modulator [NEMO]). IKK heterotrimeric holocomplex catalyzes downstream activation of nuclear factor-kappa B (NF-κB), allowing p65 (also known as RELA), a proinflammatory transcription factor, to enter the nucleus where it induces transcriptional expression of multiple proinflammatory chemokines (e.g., macrophage chemotactic protein 1 [MCP-1]), cytokines, and adhesion molecules (e.g., vascular cell adhesion molecule-1). Once activated, JNK activates c-Jun which is involved with hepatocellular cell death, and via formation of heterodimeric c-Jun:c-Fos forms the pro-inflammatory transcription factor, activator protein 1 (AP-1). In addition to TLR activation, some intracellular lipid molecules (Table 2) may result in JNK/NF-κB activation by formation of reactive oxygen species (ROS); ROS may arise from excessive β-oxidation of FFA, uncoupling of oxidative phosphorylation and mitochondrial damage caused by free cholesterol (FC) accumulation and crystallization. Alternatively, some intracellular lipids may induce endoplasmic reticulum (ER) stress, leading to JNK/NF-κB p65 activation (see Fig. 3 for more details). JNK activation can also phosphorylate insulin receptor substrates (IRS)-1 and -2, which by blocking insulin receptor signal transduction leads to insulin resistance.

TNF-α, tumor necrosis factor-α; IL-1β, interleukin-1β.

Gut Liver 2012;6:149~171 https://doi.org/10.5009/gnl.2012.6.2.149
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