A Mechanism for the Metabolic and Inflammatory Alterations Associated with Low-dose Endotoxemia
Chang, Samantha Mee
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Lipopolysaccharide (LPS), a Gram-negative endotoxin, has been well-established as the trigger for the effects of sepsis and septic shock through its binding with the innate immune receptor, Toll-like receptor 4 (TLR4). High doses of LPS signal through TLR4 to produce a massive release of pro-inflammatory cytokines including IL-6, TNFα, and other. Additionally, several recent publications have demonstrated severe metabolic alterations after LPS challenge, suppressing lipid oxidation and concurrently up-regulating glucose oxidation. Unfortunately, this switch in metabolism is inefficient for the great energy demands of the host during a systemic microbial infection which can result in vital organ failure. Meanwhile, a novel concept in several chronic disease pathologies also implicates LPS, although at very low doses. The presence of subclinically elevated circulating endotoxin levels has been termed metabolic endotoxemia and is beginning to be investigated in disease pathologies including insulin resistance and type II diabetes, atherosclerosis, cancer metastasis and Parkinson's disease. These disease phenotypes all possess a component of chronic inflammation whose source has not largely been understood, but examining the effects of very low doses of LPS may provide vital information in understanding their etiologies. However, most information on LPS signaling has been obtained using high doses of LPS (10-200ng/ml) while little to no studies have been published regarding the effects of very low doses of LPS (1pg-100pg/ml) on inflammatory and metabolic alterations. Thus, we use in vivo and in vitro models to determine that both IRAK1 and JNK are critical points of crosstalk downstream of TLR4 for the metabolic and inflammatory alterations associated with metabolic endotoxemia. Additionally, we observed significant down-regulation of nuclear receptors responsible for fatty acid metabolism, including PGC1α, PPARα, and PPARγ after very low dose LPS challenge. Further, we observe phenotypic changes in fatty acid oxidation and glucose oxidation, as well as subsequent changes in cytosolic acetyl-CoA levels and acetylation of pro-inflammatory transcription factor ATF2. Overall our studies point to several mechanisms of cross-talk between metabolism and inflammation and offer significant support to the concept of metabolic endotoxemia in the development of chronic disease.
- Doctoral Dissertations