Saturated fatty acids trigger TLR4-mediated inflammatory response

Abstract

Toll-like receptors (TLR) mediate infection-induced inflammation and sterile inflammation by endogenous molecules. Among the TLR family, TLR4 is the best understood. However, while its downstream signaling pathways have been well defined, not all ligands of TLR4 are currently known. Current evidence suggests that saturated fatty acids (SFA) act as non-microbial TLR4 agonists, and trigger its inflammatory response. Thus, our present review provides a new perspective on the potential mechanism by which SFAs could modulate TLR4-induced inflammatory responses: (1) SFAs can be recognized by CD14-TLR4-MD2 complex and trigger inflammatory pathways, similar to lipopolysaccharide (LPS). (2) SFAs lead to modification of gut microbiota with an overproduction of LPS after a high-fat intake, enhancing this natural TLR4 ligand. (3) In addition, this metabolic endotoxemia leads to an oxidative stress thereby producing atherogenic lipids - oxLDL and oxidized phospholipids - which trigger CD36-TLR4-TLR6 inflammatory response. (4) Also, the high SFA consumption increases the lipemia and the mmLDL and oxLDL formation through oxidative modifications of LDL. The mmLDL, unlike oxLDL, is involved in activation of the CD14-TLR4-MD2 inflammatory pathway. Those molecules can induce TLR4 inflammatory response by MyD88-dependent and/or MyD88-independent pathways that, in turn, promotes the expression of proinflammatory transcript factors such as factor nuclear kappa B (NF-κB), which plays a crucial role in the induction of inflammatory mediators (cytokines, chemokines, or costimulatory molecules) implicated in the development and progression of many chronic diseases.

Protective effect of quercetin on high-fat diet-induced non-alcoholic fatty liver disease in mice is mediated by modulating intestinal microbiota imbalance and related gut-liver axis activation

“…Thereby, TLR-4 expression upregulation correlated with increased LPS and fatty acids, and associated with induced de novo lipogenesis in NAFLD patients [68]. Thus, TLR-4 plays a critical role in glucose and lipid metabolism and, in turn, free fatty acids have been reported as agonists for TLR-4 [69,70], inducing activation of inflammatory transcription factors as NF-B [69]. In the present research, overexpression of TLR-4 and activation of its downstream molecules in HFD-fed mice was associated with insulin resistance and lipid metabolism gene deregulation, supporting the role of gut-liver axis-mediated TLR signaling activation on the development of steatosis in the pathogenesis of NAFLD.…”

The role of dietary fatty acid intake in inflammatory gene expression: a critical review

“…In this regard, it has been proposed that SFAs are nonmicrobial TLR agonists that promote inflammatory activation. 15 Studies have…”

Anti-Inflammatory Activity of Platycodin D on Alcohol-Induced Fatty Liver Rats via Tlr4-Myd88-Nf-

“…Research shows (Rochaa et al, 2016) that endotoxin metabolism is related to the toll-like receptor 4 (TLR4) pathway. The cluster of differentiation 14 (CD14) is best characterized for its capability to interact with endotoxin lipopolysaccharide (LPS)-binding protein (LBP) and transfer LPS to the TLR4 accessory, molecule myeloid differential protein-2 (MD-2).…”