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      3-Hydroxybutyrate as a Metabolite and a Signal Molecule Regulating Processes of Living Organisms

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          Abstract

          3-hydroxybutyrate (3-HB) as a very important metabolite occurs in animals, bacteria and plants. It is well known that in animals, 3-HB is formed as a product of the normal metabolism of fatty acid oxidation and can therefore be used as an energy source in the absence of sufficient blood glucose. In microorganisms, 3-HB mainly serves as a substrate for the synthesis of polyhydroxybutyrate, which is a reserve material. Recent studies show that in plants, 3-HB acts as a regulatory molecule that most likely influences the expression of genes involved in DNA methylation, thereby altering DNA methylation levels. Additionally, in animals, 3-HB is not only an intermediate metabolite, but also an important regulatory molecule that can influence gene expression, lipid metabolism, neuronal function, and overall metabolic rate. Some of these effects are the direct effects of 3-HB itself, while others are indirect effects, regulated by the metabolites into which 3-HB is converted. One of the most important regulatory functions of 3-HB is the inhibition of the activity of histone deacetylases and thus the epigenetic regulation of many genes. Due to the number of functions of this compound, it also shows promising therapeutic properties.

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          Most cited references155

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          Ketone body β-hydroxybutyrate blocks the NLRP3 inflammasome-mediated inflammatory disease

          Ketone bodies , β-hydroxybutyrate (BHB) and acetoacetate support mammalian survival during states of energy deficit by serving as alternative source of ATP 1 . BHB levels are elevated during starvation, high-intensity exercise or by the low carbohydrate ketogenic diet 2 . Prolonged caloric restriction or fasting reduces inflammation as immune system adapts to low glucose supply and energy metabolism switches towards mitochondrial fatty acid oxidation, ketogenesis and ketolysis 2-6 . However, role of ketones bodies in regulation of innate immune response is unknown. We report that BHB, but neither acetoacetate nor structurally-related short chain fatty acids, butyrate and acetate, suppresses activation of the NLRP3 inflammasome in response to several structurally unrelated NLRP3 activators, without impacting NLRC4, AIM2 or non-canonical caspase-11 inflammasome activation. Mechanistically, BHB inhibits NLRP3 inflammasome by preventing K+ efflux and reducing ASC oligomerization and speck formation. The inhibitory effects of BHB on NLRP3 were not dependent on chirality or classical starvation regulated mechanisms like AMPK, reactive oxygen species (ROS), autophagy or glycolytic inhibition. BHB blocked NLRP3 inflammasome without undergoing oxidation in TCA cycle, independently of uncoupling protein-2 (UCP2), Sirt2, receptor Gpr109a and inhibition of NLRP3 did not correlate with magnitude of histone acetylation in macrophages. BHB reduced the NLRP3 inflammasome mediated IL-1β and IL-18 production in human monocytes. In vivo, BHB attenuates caspase-1 activation and IL-1β secretion in mouse models of NLRP3-mediated diseases like Muckle-Wells Syndrome (MWS), Familial Cold Autoinflammatory syndrome (FCAS) and urate crystal induce body cavity inflammation. Taken together, these findings suggest that the anti-inflammatory effects of caloric restriction or ketogenic diets may be mechanistically linked to BHB-mediated inhibition of the NLRP3 inflammasome, and point to the potential use of interventions that elevate circulating BHB against NLRP3-mediated proinflammatory diseases.
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            Short-chain fatty acids and ketones directly regulate sympathetic nervous system via G protein-coupled receptor 41 (GPR41).

            The maintenance of energy homeostasis is essential for life, and its dysregulation leads to a variety of metabolic disorders. Under a fed condition, mammals use glucose as the main metabolic fuel, and short-chain fatty acids (SCFAs) produced by the colonic bacterial fermentation of dietary fiber also contribute a significant proportion of daily energy requirement. Under ketogenic conditions such as starvation and diabetes, ketone bodies produced in the liver from fatty acids are used as the main energy sources. To balance energy intake, dietary excess and starvation trigger an increase or a decrease in energy expenditure, respectively, by regulating the activity of the sympathetic nervous system (SNS). The regulation of metabolic homeostasis by glucose is well recognized; however, the roles of SCFAs and ketone bodies in maintaining energy balance remain unclear. Here, we show that SCFAs and ketone bodies directly regulate SNS activity via GPR41, a Gi/o protein-coupled receptor for SCFAs, at the level of the sympathetic ganglion. GPR41 was most abundantly expressed in sympathetic ganglia in mouse and humans. SCFA propionate promoted sympathetic outflow via GPR41. On the other hand, a ketone body, β-hydroxybutyrate, produced during starvation or diabetes, suppressed SNS activity by antagonizing GPR41. Pharmacological and siRNA experiments indicated that GPR41-mediated activation of sympathetic neurons involves Gβγ-PLCβ-MAPK signaling. Sympathetic regulation by SCFAs and ketone bodies correlated well with their respective effects on energy consumption. These findings establish that SCFAs and ketone bodies directly regulate GPR41-mediated SNS activity and thereby control body energy expenditure in maintaining metabolic homeostasis.
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              Suppression of oxidative stress by β-hydroxybutyrate, an endogenous histone deacetylase inhibitor.

              Concentrations of acetyl-coenzyme A and nicotinamide adenine dinucleotide (NAD(+)) affect histone acetylation and thereby couple cellular metabolic status and transcriptional regulation. We report that the ketone body d-β-hydroxybutyrate (βOHB) is an endogenous and specific inhibitor of class I histone deacetylases (HDACs). Administration of exogenous βOHB, or fasting or calorie restriction, two conditions associated with increased βOHB abundance, all increased global histone acetylation in mouse tissues. Inhibition of HDAC by βOHB was correlated with global changes in transcription, including that of the genes encoding oxidative stress resistance factors FOXO3A and MT2. Treatment of cells with βOHB increased histone acetylation at the Foxo3a and Mt2 promoters, and both genes were activated by selective depletion of HDAC1 and HDAC2. Consistent with increased FOXO3A and MT2 activity, treatment of mice with βOHB conferred substantial protection against oxidative stress.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Biomolecules
                Biomolecules
                biomolecules
                Biomolecules
                MDPI
                2218-273X
                09 March 2021
                March 2021
                : 11
                : 3
                : 402
                Affiliations
                Faculty of Biotechnology, University of Wroclaw, 51-148 Wroclaw, Poland; justyna.mierziak@ 123456uwr.edu.pl (J.M.); marta.burgberger@ 123456uwr.edu.pl (M.B.)
                Author notes
                Article
                biomolecules-11-00402
                10.3390/biom11030402
                8000602
                33803253
                985a5cf4-fb11-4cf8-85d3-87d29936b93c
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 03 February 2021
                : 03 March 2021
                Categories
                Review

                3-hydroxybutyrate,polyhydroxybutyrate,3-hb metabolism,signaling,animals,bacteria,plants

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