We have demonstrated that IRAK-1 plays a critical role in LPS-modulated FFA oxidation during endotoxemia. IRAK-1−/− mice do not exhibit the dramatic alteration in plasma levels of FFA and TG, and have improved survival rates following a lethal LPS challenge. Mechanistically, IRAK-1 participates in LPS-mediated suppression of key FFA oxidative genes including CPT1 and MCAD, via suppressing the transcription factors PPARα and PGC-1α.
Our finding confirms and extends previous studies demonstrating the suppressive effect of LPS on FFA oxidation (Feingold et al., 2008
; Khovidhunkit et al., 2004
). The reduced expression of key FFA oxidative genes due to the LPS challenge is most likely responsible for this effect (Feingold et al., 2008
). LPS exerts its pleiotropic effects through TLR4 and multiple downstream intracellular adaptor molecules as well as effector kinases (Su, 2005
). Given the fact that multiple pathways diverge downstream of the LPS receptor TLR4, it is likely that selected intracellular molecules may be specifically involved in suppressing the expression of FFA oxidative genes. Our current study is the first to provide solid evidence that defines IRAK-1 as a key intracellular signaling molecule involved in the suppression of FFA oxidative genes.
Mechanistically, our data reveals that IRAK-1 is required for LPS-mediated suppression of nuclear receptors (PPARα and PGC-1α), necessary for the active expression of CPT-1 and MCAD (). However, the means by which IRAK-1 related downstream signaling processes lead to reduced levels of PPARα and PGC-1α remains unknown. Several potential possibilities for the reduced levels of these nuclear receptors, including reduced transcription and/or translation, and elevated protein degradation, may be involved (Blanquart et al., 2003
; Blanquart et al., 2004
). In particular, ubiquitin-mediated degradation of PPAR has been previously reported (Blanquart et al., 2002
). Moreover, IRAK-1 and its associated molecules such as TRAF6 and Tollip are known to be involved in protein ubiquitination and degradation (Brissoni et al., 2006
; Conze et al., 2008
; Didierlaurent et al., 2006
). Further biochemical analyses using cultured cell lines are warranted to test whether LPS may trigger degradation of PPARα and/or PGC-1α via a pathway involving IRAK-1.
A schematic illustration of LPS-mediated regulation of FFA oxidation
This study provides a potential therapeutic target for the development of anti-septic therapies. There is currently no effective drug available to treat sepsis, due to the complex inflammatory and metabolic complications involved in this syndrome. Antibiotics, fluid therapy, and corticosteroids remain the mainstay of sepsis treatment, but these administrations remain supportive at best. Additionally, therapies solely targeting inflammatory cytokines such as TNFα or IL-1β have all failed clinical testing in the past (Abraham et al., 1998
; Abraham et al., 1995
; Goode et al., 2006
). It is likely that interventions in both inflammatory and metabolic alterations are necessary in the prevention of devastating multi-organ failure that ensues following severe disseminated endotoxemia. Thus, compounds that could potentially inactivate IRAK-1, combined with anti-inflammatory agents, may be useful in treating sepsis.