Metabolic endotoxemia: a molecular link between obesity and cardiovascular risk

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   Figure 1

   LPS-induced TLR4 activation induces the transcription of pro-inflammatory mediators, via the recruitment of adaptor molecules such as MyD88 and TRIF. LPS is mainly sensed through the activation of TLR4 by the LBP–LPS trigger complex. CD14 and MD-2 are critical elements in this receptor complex giving it responsiveness to LPS. TLR4 activation provokes the recruitment of four adaptor molecules, including MyD88 and TRIF. MyD88 activates the IKK complex via IRAK kinases/TRAF recruitment, lately leading to NFκB diffusion to the nucleus. TRAF6 activation also promotes MAPK activation and nuclear translocation, also inducing the transcription of pro-inflammatory cytokines. NFκB transcription also occurs in a MyD88-dependent pathway, via TRIF-mediated activation of the kinases TBK1 and RIP1. Full color version of this figure available via http://dx.doi.org/10.1530/JME-13-0079
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   Figure 2

   The gut epithelium is an efficient barrier that prevents absorption of LPS derived from Gram-negative gut microbiota. Obesity, high-fat diet, diabetes, and NAFLD are associated with higher gut permeability leading to metabolic endotoxemia. Probiotics, prebiotics, and antibiotic treatment can reduce LPS absorption and plasmatic levels. LPS in the bloodstream is transported by lipoproteins and LBP. In the liver, LPS is cleared by hepatocytes and excreted in the bile. LPS promotes hepatic insulin resistance, hypertriglyceridemia, hepatic triglyceride accumulation, and secretion of pro-inflammatory cytokines promoting the progression of fatty liver disease. In the endothelium, LPS induces the expression of pro-inflammatory, chemotactic, and adhesion molecules, which promotes atherosclerosis development and progression. In the adipose tissue, LPS induces adipogenesis, insulin resistance, macrophage infiltration, oxidative stress, and release of pro-inflammatory cytokines and chemokines. Full color version of this figure available via http://dx.doi.org/10.1530/JME-13-0079

• © 2013 Society for Endocrinology