期刊
ONCOTARGET
卷 7, 期 41, 页码 66444-66454出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.12119
关键词
beta-hydroxybutyrate; endoplasmic reticulum; aging; inflammasome; AMPK; Gerotarget
资金
- National Research Foundation of Korea (NRF) - Korea Government (MSIP) [2009-0083538]
beta-Hydroxybutyrate, a ketone body that is used as an energy source in organs such as the brain, muscle, and heart when blood glucose is low, is produced by fatty acid oxidation in the liver under the fasting state. Endoplasmic reticulum (ER) stress is linked with the generation of intracellular reactive oxygen species and the accumulation of misfolded protein in the ER. ER stress is known to induce the NOD-like receptor protein 3 inflammasome, which mediates activation of the proinflammatory cytokine interleukin-1 beta, whose maturation is caspase-1-dependent. We investigated whether beta-hydroxybutyrate modulates ER stress, inflammasome formation, and insulin signaling. Sprague Dawley rats (6 and 24 months of age) that were starved for 3 d and rats treated with beta-hydroxybutyrate (200 mg . kg(-1) . d(-1) i.p., for 5 d) were used for in vivo investigations, whereas human hepatoma HepG2 cells were used for in vitro studies. Overexpression of AMPK in cultured cells was performed to elucidate the molecular mechanism. The starvation resulted in increased serum beta-hydroxybutyrate levels with decreased ER stress (PERK, IRE1, and ATF6a) and inflammasome (ASC, caspase-1, and NLRP3) formation compared with non-fasted 24-month-old rats. In addition, beta-hydroxybutyrate suppressed the increase of ER stress-and inflammasome-related marker proteins. Furthermore, beta-hydroxybutyrate treatment increased the expression of manganese superoxide dismutase and catalase via the AMP-activated protein kinase-forkhead box protein O3a transcription factor pathway both in vivo and in vitro. The significance of the current study was the discovery of the potential therapeutic role of beta-hydroxybutyrate in suppressing ER-stress- induced inflammasome formation.
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