The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease

Youm, Yun‐Hee; Nguyen, Kim Thuy; Grant, Ryan W.; Goldberg, Emily L.; Bodogai, Monica; Kim, Dongin; D’Agostino, Dominic P.; Planavsky, Noah J.; Lupfer, Christopher R.; Kanneganti, Thirumala‐Devi; Kang, Sangmo; Horváth, Tamas L.; Fahmy, Tarek M.; Crawford, Peter A.; Biragyn, Arya; Alnemri, Emad S.; Dixit, Vishwa Deep

doi:10.1038/nm.3804

Cited by 1,442 publications

(1,120 citation statements)

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“…Mice fed with ketogenic diets demonstrate elevated HMGCS2/βHB levels in tissues including the intestine. 29, 30 1,3-Butanediol, a ketone body precursor, is metabolized by alcohol dehydrogenase and aldehyde dehydrogenases to βHB. 31 We fed mice with a ketogenic diet (normal chow diet mixed with 1,3-butanediol ketone diesters) 30 for 14 days to increase ketogenesis; the intestinal tissues were then harvested for analysis.…”

Section: Resultsmentioning

confidence: 99%

“…29, 30 1,3-Butanediol, a ketone body precursor, is metabolized by alcohol dehydrogenase and aldehyde dehydrogenases to βHB. 31 We fed mice with a ketogenic diet (normal chow diet mixed with 1,3-butanediol ketone diesters) 30 for 14 days to increase ketogenesis; the intestinal tissues were then harvested for analysis. As shown in Figure 6a, mice fed with the ketogenic diet demonstrated inhibition of HDAC as noted by the increased expression of H3K9ac.…”

Section: Resultsmentioning

confidence: 99%

“…34 To model a ketogenic diet and elevate ketogenesis in vivo, we fed mice with 1,3-butanediol ketone diesters. 30 Ten mice (male, 16 weeks) were randomized to control diet versus ketogenic diet groups. To prepare the ketogenic diet, standard chow food pellets were ground in a mixer, 200 g of ground diet was mixed with 50 ml of ( ± )-1,3-Butanediol (B84785, Sigma-Aldrich) and shaken to form round pellets.…”

Section: Methodsmentioning

confidence: 99%

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Ketogenesis contributes to intestinal cell differentiation

et al. 2016

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The intestinal epithelium undergoes a continual process of proliferation, differentiation and apoptosis. Previously, we have shown that the PI3K/Akt/mTOR pathway has a critical role in intestinal homeostasis. However, the downstream targets mediating the effects of mTOR in intestinal cells are not known. Here, we show that the ketone body β-hydroxybutyrate (βHB), an endogenous inhibitor of histone deacetylases (HDACs) induces intestinal cell differentiation as noted by the increased expression of differentiation markers (Mucin2 (MUC2), lysozyme, IAP, sucrase-isomaltase, KRT20, villin, Caudal-related homeobox transcription factor 2 (CDX2) and p21 Waf1 ). Conversely, knockdown of the ketogenic mitochondrial enzyme hydroxymethylglutaryl CoA synthase 2 (HMGCS2) attenuated spontaneous differentiation in the human colon cancer cell line Caco-2. Overexpression of HMGCS2, which we found is localized specifically in the more differentiated portions of the intestinal mucosa, increased the expression of CDX2, thus further suggesting the contributory role of HMGCS2 in intestinal differentiation. In addition, mice fed a ketogenic diet demonstrated increased differentiation of intestinal cells as noted by an increase in the enterocyte, goblet and Paneth cell lineages. Moreover, we showed that either knockdown of mTOR or inhibition of mTORC1 with rapamycin increases the expression of HMGCS2 in intestinal cells in vitro and in vivo, suggesting a possible cross-talk between mTOR and HMGCS2/βHB signaling in intestinal cells. In contrast, treatment of intestinal cells with βHB or feeding mice with a ketogenic diet inhibits mTOR signaling in intestinal cells. Together, we provide evidence showing that HMGCS2/βHB contributes to intestinal cell differentiation. Our results suggest that mTOR acts cooperatively with HMGCS2/βHB to maintain intestinal homeostasis.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Ketogenesis contributes to intestinal cell differentiation

et al. 2016

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“…Bone Marrow-derived Macrophage (BMDMs) and Cell Culture-The BMDMs were prepared, and inflammasome activation assays were performed as described by us previously (13,32). All steps were performed using sterile technique.…”

Section: Methodsmentioning

confidence: 99%

Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity

Camell¹,

Nguyen²,

Jurczak³

et al. 2015

Journal of Biological Chemistry

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Dietary lipid overload and calorie excess during obesity is a low grade chronic inflammatory state with diminished ability to appropriately metabolize glucose or lipids. Macrophages are critical in maintaining adipose tissue homeostasis, in part by regulating lipid metabolism, energy homeostasis, and tissue remodeling. During high fat diet-induced obesity, macrophages are activated by lipid derived "danger signals" such as ceramides and palmitate and promote the adipose tissue inflammation in an Nlrp3 inflammasome-dependent manner. Given that the metabolic fate of fatty acids in macrophages is not entirely elucidated, we have hypothesized that de novo synthesis of ceramide, through the rate-limiting enzyme serine palmitoyltransferase long chain (Sptlc)-2, is required for saturated fatty aciddriven Nlrp3 inflammasome activation in macrophages. Here we report that mitochondrial targeted overexpression of catalase, which is established to mitigate oxidative stress, controls ceramide-induced Nlrp3 inflammasome activation but does not affect the ATP-mediated caspase-1 cleavage. Surprisingly, myeloid cell-specific deletion of Sptlc2 is not required for palmitatedriven Nlrp3 inflammasome activation. Furthermore, the ablation of Sptlc2 in macrophages did not impact macrophage polarization or obesity-induced adipose tissue leukocytosis. Consistent with these data, investigation of insulin resistance using hyperinsulinemic-euglycemic clamps revealed no significant differences in obese mice lacking ceramide de novo synthesis machinery in macrophages. These data suggest that alternate metabolic pathways control fatty acid-derived ceramide synthesis in macrophage and the Nlrp3 inflammasome activation in obesity. Diet-induced obesity (DIO)2 is a growing epidemic and has greatly augmented the number of humans diagnosed with metabolic diseases such as type 2 diabetes, cardiovascular disease, and atherosclerosis (1, 2). The importance of inflammation in driving metabolic dysregulation during DIO is well established, and research has highlighted the importance of the adipose tissue and resident immune cells in maintaining glucose homeostasis (3, 4).DIO induces adipose tissue inflammation that is largely characterized by infiltration of immune cells, including pro-inflammatory activated macrophages, T cells, and B cells (5-8). In lean adipose, resident macrophages exhibit anti-inflammatory characteristics, including expressing surface markers such as MGL1, CD206, and Arginase1. In contrast, infiltrating macrophages express increased amounts of inflammatory cytokines, such as TNF␣, MCP1, and IL1␤ (7). Infiltrating CCR2 ϩ macrophages surround dying adipocytes, forming crown-like structures, and contain large lipid droplets (9, 10), suggesting they are uniquely sensitive to the lipid-loaded microenvironment. Diet-induced inflammation is mediated through the activation of the NLRP3 (NLR family pyrin domain containing 3) inflammasome, a large cytosolic multiprotein scaffolding complex that activates caspase-1 and leads to the secretion...

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“…Since proteasome degradation and autophagy are anti-inflammatory possible interventions may involve enhancing these pathways to effectively reduce NLRP3 activation and inflammation. Small molecules that can directly block the NLRP3 inflammasome and related signalling pathways have recently shown promise in pre-clinical studies [160,161]. Clinical trials of agents designed to modulate proteotoxic stress and the inflammasome, in combination with traditional therapies, will determine the therapeutic impact of these new insights into the connections between protein homeostasis and autoinflammation.…”

Section: Conclusion and Implications For Future Therapiesmentioning

confidence: 99%

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

et al. 2015

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Cells have a number of mechanisms to maintain protein homeostasis, including proteasomemediated degradation of ubiquitinated proteins and autophagy, a regulated process of 'self-eating' where the contents of entire organelles can be recycled for other uses. The unfolded protein response prevents protein overload in the secretory pathway. In the past decade, it has become clear that these fundamental cellular processes also help contain inflammation though degrading pro-inflammatory protein complexes such as the NLRP3 inflammasome. Signaling pathways such as the UPR can also be co-opted by tolllike receptor and mitochondrial reactive oxygen species signaling to induce inflammatory responses.Mutations that alter key inflammatory proteins, such as NLRP3 or TNFR1, can overcome normal protein homeostasis mechanisms, resulting in autoinflammatory diseases. Conversely, Mendelian defects in the proteasome cause protein accumulation, which can trigger interferon-dependent autoinflammatory disease. In non-Mendelian inflammatory diseases, polymorphisms in genes affecting the UPR or autophagy pathways can contribute to disease, and in diseases not formerly considered inflammatory such as neurodegenerative conditions and type 2 diabetes, there is increasing evidence that cell intrinsic or environmental alterations in protein homeostasis may contribute to pathogenesis.3 Cells must maintain a delicate balance between the demands for protein synthesis and the need to avoid accumulation of incompletely processed or unfolded proteins that can accumulate under normal conditions and even more so when cells face a variety of stresses. The unfolded protein response (UPR) is an evolutionarily conserved mechanism to maintain cellular homeostasis by preventing the accumulation of misfolded proteins in the endoplasmic reticulum (ER). Disturbed protein folding in the ER is primarily detected by three transmembrane (TM) proteins: activating transcription factor 6 (ATF6), inositol-requiring transmembrane kinase/endonuclease 1 (IRE1) and pancreatic ER kinase (PERK). The combined action of these sensors reduces global protein synthesis while upregulating the production of chaperone proteins that can stabilize misfolded proteins. Apart from ER homeostasis, the UPR can modulate other biological functions, including apoptosis, protein secretion, and as we will discuss further, inflammatory responses [1,2].A series of molecular changes are initiated in response to cellular stressors in order to minimize damage caused by unfavorable environmental conditions, such as temperature changes, toxins (e.g. bacterial, chemical), radiation, mechanical damage, nutritional status as well as incompletely folded proteins intracellularly (Figure 1). The UPR serves the adaptive purpose of protecting the cell by activating a series of mechanisms including the induction of molecular chaperones to assist with correct folding -e.g. heat shock proteins and foldases. Interestingly there are a number of connections between the UPR and inflammatory signaling pat...

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The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome–mediated inflammatory disease

Cited by 1,442 publications

References 35 publications

Ketogenesis contributes to intestinal cell differentiation

Ketogenesis contributes to intestinal cell differentiation

Macrophage-specific de Novo Synthesis of Ceramide Is Dispensable for Inflammasome-driven Inflammation and Insulin Resistance in Obesity

Protein misfolding and dysregulated protein homeostasis in autoinflammatory diseases and beyond

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