Oncotarget

Research Papers: Gerotarget (Focus on Aging):

β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation

Ha Ram Bae, Dae Hyun Kim, Min Hi Park, Bonggi Lee, Min Jo Kim, Eun Kyeong Lee, Ki Wung Chung, Seong Min Kim, Dong Soon Im and Hae Young Chung _

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Oncotarget. 2016; 7:66444-66454. https://doi.org/10.18632/oncotarget.12119

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Abstract

Ha Ram Bae1,*, Dae Hyun Kim1,*, Min Hi Park1, Bonggi Lee1, Min Jo Kim1, Eun Kyeong Lee1, Ki Wung Chung1, Seong Min Kim1, Dong Soon Im1 and Hae Young Chung1

1 Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea

* These authors have contributed equally to this work

Correspondence to:

Hae Young Chung, email:

Keywords: β-hydroxybutyrate; endoplasmic reticulum; aging; inflammasome; AMPK; Gerotarget

Received: May 10, 2016 Accepted: August 26, 2016 Published: September 19, 2016

Abstract

β-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-1β, whose maturation is caspase-1-dependent. We investigated whether β-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 β-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 β-hydroxybutyrate levels with decreased ER stress (PERK, IRE1, and ATF6α) and inflammasome (ASC, caspase-1, and NLRP3) formation compared with non-fasted 24-month-old rats. In addition, β-hydroxybutyrate suppressed the increase of ER stress- and inflammasome-related marker proteins. Furthermore, β-hydroxybutyrate treatment increased the expression of manganese superoxide dismutase and catalase via the AMP-activated protein kinase-forkhead box protein O3α transcription factor pathway both in vivo and in vitro. The significance of the current study was the discovery of the potential therapeutic role of β-hydroxybutyrate in suppressing ER-stress-induced inflammasome formation.


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