Leukotriene B4 as a Potential Therapeutic Target for the Treatment of Metabolic Disorders

In the last decade, the incidence of metabolic disorders has increased drastically worldwide and is becoming a global health threat. Studies have shown that the pathogenesis and co-morbidities of diseases such as diabetes, gout, and atherosclerosis involve chronic low-grade inflammation and metabolic changes (1). As this inflammation is triggered by endogenous substances, instead of pathogens, it is called “sterile inflammation”. Chronic low-grade inflammation can be triggered by the accumulation of metabolic products such as uric acid, glucose, cholesterol, and free circulating fatty acids. These substances can induce inflammation by two distinct mechanisms: (1) engagement of Toll-Like Receptors (TLR), such as TLR-2 (2), TLR-4 (3), and TLR-9 (4) and (2) activation of the intracellular receptor complex known as inflammasome that leads to caspase-1 activation, an enzyme that cleaves prointerleukin (IL)-1β into its active form (5–7). IL-1β acts on its receptor IL1R1, a member of the TLR family whose activation is dependent on the presence of the adaptor molecule Myeloid Differentiation primary response gene 88 (MyD88). Although TLR-2 signaling is mediated mainly through the MyD88, TLR-4 activates MyD88-dependent and TIR-domaincontaining adapter-inducing interferon β (TRIF)-dependent pathways. The MyD88-dependent pathway culminates in the activation of the Nuclear Factor kappa B (NFκB)/Activator Protein (AP) 1 and the TRIF-dependent pathway leads to delayed activation of NFκB associated with Interferon Regulatory Factor (IRF) (8). Thus, NFκB is a transcription factor of several genes involved in inflammation and also regulates its own transcription (9). In metabolic diseases with chronic lowgrade inflammation, NFκB is continuously activated (10). Since NFκB can be activated through the adaptor molecule MyD88, modulation of its expression should have important consequences on the inflammatory response. Leukotrienes are lipid mediators whose production is increased during inflammation. Activated phospholipase A2 releases arachidonic acid from membrane phospholipids. Liberated (soluble) arachidonic acid can be metabolized by 5-lipoxygenase (5-LO) to produce leukotrienes including LTB4 and cysteinyl leukotrienes, LTC4, LTD4, and LTE4. It is well documented that leukotrienes are mediators of inflammatory events such as edema and leukocyte infiltration and activation and that they have an essential role in acute and chronic inflammatory diseases. Leukotrienes were also shown to mediate resistance to infections by several microorganisms (11). In macrophages, leukotrienes were shown to potentiate phagocytosis and microbicidal activity by affecting the mechanisms involved in actin polymerization and activation of NADPH oxidase, respectively (12). LTB4 binds to two distinct G protein-coupled receptors. The Leukotriene Receptor (BLT)1 is the high affinity receptor that induces inflammation, enhances cytokine production, phagocytosis, and mediates antimicrobial effector functions. Through BLT1, LTB4 was shown to enhance MyD88 expression and potentiate MyD88-dependent stimuli responses while no difference on MyD88-independent stimuli was found (13). BLT2 binds LTB4 with lower affinity and has