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.

Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics

“…βOHB and exogenous nicotinic acid (Taggart et al, 2005), both confer anti-inflammatory effects in TNFα or LPS-induced inflammation by decreasing the levels of pro-inflammatory proteins (iNOS, COX-2), or secreted cytokines (TNFα, IL-1β, IL-6, CCL2/MCP-1), in part through inhibiting NF-κB translocation (Fu et al, 2014; Gambhir et al, 2012). βOHB decreases ER stress and the NLRP3 inflammasome, activating the antioxidative stress response (Bae et al, 2016; Youm et al, 2015). However, in neurodegenerative inflammation, GPR109A-dependent βOHB-mediated protection does not involve inflammatory mediators like MAPK pathway signaling ( e.g.…”

NLRP3 Inflammasome in Neurological Diseases, from Functions to Therapies

“…Experiments showed that BHB decreased K + efflux and endoplasmic reticulum stress (Youm et al, 2015; Bae et al, 2016). Furthermore, BHB is transported to brain parenchyma and plays a neuroprotective role under several pathological conditions (Orhan et al, 2015; Xie et al, 2015).…”

Complement and human T cell metabolism: Location, location, location

“…107 The impact of lectin pathways proteins on mitochondrial activity, however, remains to be defined. Importantly, metabolic by-products and particularly those generated during quiescent states or during contracting and tolerogenic response phases, such as AMP, β-hydroxybutyrate, 108,109 and prostaglandin E2 110 can also function as resolution-associated molecular patterns (RAMPs), 111 inhibit NLRP3 inflammasome activation, and contribute to the cessation of cell effector functions.…”