ATF4 Plays Critical Roles in Saturated Fatty Acid-induced IL-6 Expression in Macrophages

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 649-659-Basic Mechanisms of Obesity
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-651
Yorihiro Iwasaki, Takayoshi Suganami, Rumi Hachiya, Ibuki Shirakawa, Miho Hamaguchi and Yoshihiro Ogawa*
Tokyo Med and Dental University, Japan
Chronic inflammation is a pathophysiological basis of the metabolic syndrome in which saturated fatty acids (SFAs) play essential roles as pro-inflammatory mediators. To date, the mechanism of SFA-induced inflammation has been explained by Toll-like receptor 4 (TLR4)-mediated signaling pathways. Hereby we focus on a novel TLR4-independent mechanism of SFA-induced interleukin-6 (IL-6) expression. Using TLR4-/- macrophages, we performed microarray analysis to identify signaling pathways activated by palmitate, a representative SFA. Pathway analysis of microarray data revealed that palmitate potently activated pathways downstream of activating transcription factor 4 (ATF4) and nuclear factor-κB (NF-κB). We next examined the role of ATF4 in inflammatory cytokine expression using ATF4+/- macrophages. ATF4+/- macrophages were defective in palmitate-induced IL-6 expression compared to wild type macrophages. Conversely, ATF4 overexpression resulted in enhanced IL-6 expression induced by lipid A, a TLR4 agonist, in a synergistic manner. Endoplasmic stress inducers also exaggerated lipid A-induced IL-6 expression in an ATF4-dependent manner. A chromatin immunoprecipitation assay showed ATF4 recruitment to the IL-6 promoter. Furthermore, we found that ATF4+/- macrophages were defective in NF-κB activation. Collectively, these results suggest that ATF4 has critical roles in SFA-induced IL-6 expression.

Nothing to Disclose: YI, TS, RH, IS, MH, YO

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