Aspartate alleviates liver injury and regulates mRNA expressions of TLR4 and NOD signaling-related genes in weaned pigs after lipopolysaccharide challenge.

Pro-inflammatory cytokines play a critical role in many models of liver injury. In addition, aspartate (Asp) plays an important role in many biological and physiological processes including liver physiology. We hypothesized that Asp could alleviate lipopolysaccharide (LPS)-induced liver injury. Forty-eight weanling pigs were assigned to four treatments including: (1) non-challenged control; (2) LPS challenged control; (3) LPS+0.5% Asp; (4) LPS+1.0% Asp. After 20-d feeding with control (0% Asp), 0.5% or 1.0% Asp supplemented diets, pigs were injected with saline or LPS. At 4 (early phase) and 24 h (late phase) post-injection, blood and liver samples were obtained. Asp attenuated liver injury indicated by reduced serum aspartate aminotransferase activity and increased ratio of serum alanine aminotransferase and aspartate aminotransferase at 24 h, and less severe histological liver damage induced by LPS challenge at 4 or 24 h. In addition, Asp supplementation to LPS challenged pigs decreased mRNA expressions of tumor necrosis factor (TNF)-α and cyclooxygenase-2 linearly and quadratically at 4 h, and increased mRNA expressions of these pro-inflammatory mediators linearly and quadratically at 24 h. Finally, Asp decreased mRNA expression of toll-like receptor 4 (TLR4) signaling related genes (TLR4, myeloid differentiation factor 88, IL-1 receptor-associated kinase 1, TNF-α receptor-associated factor (6), nucleotide-binding oligomerization domain protein (NOD) signaling related genes (NOD1, NOD2 and receptor-interacting serine/threonine-protein kinase 2) and nuclear factor-κB p65 linearly or quadratically at 4 h. However, Asp increased mRNA expressions of these signaling molecules linearly or quadratically at 24 h. These results indicate that, at early and late phases of LPS challenge, Asp exerts opposite regulatory effects on mRNA expression of hepatic pro-inflammatory cytokines and TLR4 and NOD signalling related genes, and improves liver integrity.

Modulation of pattern recognition receptor-mediated inflammation and risk of chronic diseases by dietary fatty acids.

Chronic inflammation is known to promote the development of many chronic diseases. Pattern recognition receptors (PRRs), Toll-like receptors (TLRs), and nucleotide-binding oligomerization domain proteins (NODs) mediate both infection-induced inflammation and sterile inflammation by recognizing pathogen- associated molecular patterns and endogenous molecules, respectively. PRR-mediated inflammation is an important determinant in altering the risk of many chronic diseases. Saturated fatty acids (SFAs) can activate PRRs, leading to enhanced expression of pro-inflammatory target gene products. However, n-3 polyunsaturated fatty acids (PUFAs) inhibit agonist-induced activation of PRRs. These results suggest that SFAs and n-3 PUFAs can reciprocally modulate PRR-mediated inflammation, and that PRRs and their downstream signaling components are molecular targets for dietary strategies to reduce chronic inflammation and subsequent risk of chronic diseases. This advancement in knowledge provides a new paradigm for understanding the mechanism by which different dietary fatty acids modify risk of chronic diseases including insulin resistance, atherosclerosis, and cancer.