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The Role of Interleukin 1 Receptor Associated Kinase 1 (IRAK1) in lipid metabolic alterations associated with endotoxemia
Author(s) -
Chang Samantha Mee,
Maitra Urmila,
Li Liwu
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.476.2
Subject(s) - tlr4 , lipid metabolism , lipopolysaccharide , endocrinology , receptor , medicine , kinase , pyruvate dehydrogenase complex , carnitine , septic shock , biology , biochemistry , enzyme , sepsis
Both inflammatory and metabolic alterations have been established in the pathology of endotoxemia and septic shock, making treatment very difficult. The metabolic alterations associated with endotoxemia contribute to multiple organ failure (MOF) and high mortality rate in septic patients. However, the mechanism behind the shift in metabolism during lipopolysaccharide (LPS) ‐mediated endotoxemia has not been defined. In this study, we examine the role of Interleukin 1 receptor associated kinase 1 (IRAK1), a kinase downstream of the innate LPS receptor Toll‐like receptor 4 (TLR4), in the lipid metabolic alterations associated with LPS. We report a decrease in fatty acid oxidation (FAO) and an increase in plasma levels of free fatty acid (FFA) and triglyceride (TG) in WT but not IRAK1 −/− mice injected with a lethal dose of LPS (25mg/kg). Mechanistically, we demonstrate that LPS suppresses FAO by decreasing the expression of mitochondrial β‐oxidation enzymes including carnitine palmitoyl transferase 1□ (CPT1□) and medium chain acyl dehydrogenase (MCAD), as well as pyruvate dehydrogenase kinase 4 (PDK4). Additionally, LPS suppressed the levels of nuclear receptors PPAR□ and PGC‐1□ in tissues from WT but not IRAK1 −/− mice after lethal LPS injection. In conclusion, this study establishes that IRAK1 plays a novel role in the lipid metabolic alterations associated with TLR4 stimulation by LPS. Research funded by the NIH T32 Program, mentorship provided by Dr. Liwu Li, member of the ASBMB.