title: β-Hydroxybutyrate suppresses inflammasome formation by ameliorating endoplasmic reticulum stress via AMPK activation.
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.
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Ha Ram
authors.initials: HR
authors.lastname: Bae
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Dae Hyun
authors.initials: DH
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Min Hi
authors.initials: MH
authors.lastname: Park
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Bonggi
authors.initials: B
authors.lastname: Lee
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Min Jo
authors.initials: MJ
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Eun Kyeong
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Ki Wung
authors.initials: KW
authors.lastname: Chung
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Seong Min
authors.initials: SM
authors.lastname: Kim
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Dong Soon
authors.initials: DS
authors.lastname: Im
authors.affiliation: Molecular Inflammation Research Center for Aging Intervention, College of Pharmacy, Pusan National University, Geumjeong-gu, Busan, Republic of Korea.
authors.forename: Hae Young
authors.initials: HY
authors.lastname: Chung
mesh_terms: D020155:3-Hydroxybutyric Acid / Q000494:pharmacology*; D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D004789:Enzyme Activation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D058847:Inflammasomes / Q000187:drug effects*; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D058847:Inflammasomes; D055372:AMP-Activated Protein Kinases; D020155:3-Hydroxybutyric Acid
keywords: AMPK; Gerotarget; aging; endoplasmic reticulum; inflammasome; β-hydroxybutyrate