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International Journal of Molecular... Dec 2023Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through... (Review)
Review
Ketone bodies (KBs), such as acetoacetate and β-hydroxybutyrate, serve as crucial alternative energy sources during glucose deficiency. KBs, generated through ketogenesis in the liver, are metabolized into acetyl-CoA in extrahepatic tissues, entering the tricarboxylic acid cycle and electron transport chain for ATP production. Reduced glucose metabolism and mitochondrial dysfunction correlate with increased neuronal death and brain damage during cerebral ischemia and neurodegeneration. Both KBs and the ketogenic diet (KD) demonstrate neuroprotective effects by orchestrating various cellular processes through metabolic and signaling functions. They enhance mitochondrial function, mitigate oxidative stress and apoptosis, and regulate epigenetic and post-translational modifications of histones and non-histone proteins. Additionally, KBs and KD contribute to reducing neuroinflammation and modulating autophagy, neurotransmission systems, and gut microbiome. This review aims to explore the current understanding of the molecular mechanisms underpinning the neuroprotective effects of KBs and KD against brain damage in cerebral ischemia and neurodegenerative diseases, including Alzheimer's disease and Parkinson's disease.
Topics: Humans; Ketone Bodies; Neurodegenerative Diseases; Neuroprotection; Neuroprotective Agents; Diet, Ketogenic; Cerebral Infarction; Brain Injuries
PubMed: 38203294
DOI: 10.3390/ijms25010124 -
Heliyon Nov 2023Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression...
BACKGROUND
Ketone bodies are pleotropic metabolites that play important roles in multiple biological processes ranging from bioenergetics to inflammation regulation via suppression of the NLRP3 inflammasome, and epigenetic modifications. Ketone bodies are elevated in left ventricular failure (LVF) and multiple approaches that increase ketone concentrations exert advantageous cardiac effects in rodents and humans. However, the relationships between ketone bodies and right ventricular failure (RVF) are relatively unexplored.
METHODS
51 PAH patients were dichotomized into preserved or impaired RV function based on a cardiac index of 2.2 L/min/m. Impaired RV function patients were further segmented into intermediate or severe RV dysfunction based on a right atrial pressure of 8 mm Hg. Serum ketone bodies acetoacetate (AcAc) and beta-hydroxybutyrate (βOHB) were quantified using ultra performance liquid chromatography and mass spectrometry. In rodent studies, male Sprague Dawley rats were assigned to three groups: control (saline injection), monocrotaline (MCT) standard chow diet (MCT-Standard), and MCT ketogenic diet (MCT-Keto). Immunoblots and confocal microscopy probed macrophage NLRP3 activation in RV extracts and sections. RV fibrosis was determined by Picrosirus Red. Echocardiography evaluated RV function. Pulmonary arteriole remodeling was assessed from histological specimens.
RESULTS
Human RVF patients lacked a compensatory ketosis as serum AcAc and βOHB levels were not associated with hemodynamic, echocardiographic, or biochemical measures of RV dysfunction. In rodent studies, AcAc and βOHB levels were also not elevated in MCT-mediated RVF, but the ketogenic diet significantly increased AcAc and βOHB levels. MCT-Keto exhibited suppressed NLRP3 activation with a reduction in NLRP3, ASC (apoptosis-associated speck-like protein), pro-caspase-1, and interleukin-1 beta on immunoblots. Moreover, the number of ASC-positive macrophage in RV sections was reduced, RV fibrosis was blunted, and RV function was augmented in MCT-Keto rats.
CONCLUSION
The ketogenic response is blunted in pulmonary arterial hypertension (PAH) patients with RVF. In the MCT rat model of PAH-mediated RVF, a dietary-induced ketosis improves RV function, suppresses NLRP3 inflammasome activation, and combats RV fibrosis. The summation of these data suggest ketogenic therapies may be particularly efficacious in RVF, and therefore future studies evaluating ketogenic interventions in human RVF are warranted.
PubMed: 38058654
DOI: 10.1016/j.heliyon.2023.e22227 -
Metabolites Nov 2021Renal cell carcinoma (RCC) is the most common form of kidney malignancy. RCC is more common among men with a 2/1 male/female incidence ratio worldwide. Given the...
Renal cell carcinoma (RCC) is the most common form of kidney malignancy. RCC is more common among men with a 2/1 male/female incidence ratio worldwide. Given the underlying epidemiological differences in the RCC incidence between males and females, we explored the gender specific H NMR serum metabolic profiles of RCC patients and their matched controls. A number of differential metabolites were shared by male and female RCC patients. These RCC specific changes included lower lactate, threonine, histidine, and choline levels together with increased levels of pyruvate, -acetylated glycoproteins, beta-hydroxybutyrate, acetoacetate, and lysine. Additionally, serum lactate/pyruvate ratio was a strong predictor of RCC status regardless of gender. Although only moderate changes in metabolic profiles were observed between control males and females there were substantial gender related differences among RCC patients. Gender specific metabolic features associated with RCC status were identified suggesting that different metabolic panels could be leveraged for a more precise diagnostic.
PubMed: 34822425
DOI: 10.3390/metabo11110767 -
Antioxidants (Basel, Switzerland) Sep 2023In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias,...
In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.
PubMed: 37760052
DOI: 10.3390/antiox12091749 -
Lakartidningen Oct 2017Alcoholic ketoacidosis - a review A chronic alcoholic with severe metabolic acidosis presents a difficult diagnostic problem in the emergency room. Over and above... (Review)
Review
Alcoholic ketoacidosis - a review A chronic alcoholic with severe metabolic acidosis presents a difficult diagnostic problem in the emergency room. Over and above methanol- and ethylene glycol intoxication, alcoholic ketoacidosis is a common but less recognized etiology. The disorder occurs in alcoholics who have had a recent binge drinking followed by the abrupt cessation of alcohol consumption because of abdominal pain and vomiting, with resulting dehydration, starvation, and then a β-hydroxybutyrate dominated ketoacidosis. Laboratory results may be misleading as the common urine-ketone tests may be negative or only weakly positive, since they only respond to acetoacetate. The short-term prognosis is good if treatment including replacement of fluid, electrolytes, glucose and thiamine is provided. However, recent studies have indicated that alcoholic ketoacidosis may be a significant cause of mortality in patients with alcohol dependence.
Topics: Alcoholism; Disease Management; Humans; Ketones; Ketosis
PubMed: 28994854
DOI: No ID Found -
Journal of Atherosclerosis and... Dec 2023Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements... (Review)
Review
Ketone bodies, consisting of beta-hydroxybutyrate, acetoacetate, and acetone, are metabolic byproducts known as energy substrates during fasting. Recent advancements have shed light on the multifaceted effects of ketone body metabolism, which led to increased interest in therapeutic interventions aimed at elevating ketone body levels. However, excessive elevation of ketone body concentration can lead to ketoacidosis, which may have fatal consequences. Therefore, in this review, we aimed to focus on the latest insights on ketone body metabolism, particularly emphasizing its association with mitochondria as the primary site of interaction. Given the distinct separation between ketone body synthesis and breakdown pathways, we provide an overview of each metabolic pathway. Additionally, we discuss the relevance of ketone bodies to conditions such as nonalcoholic fatty liver disease or nonalcoholic steatohepatitis and cardiovascular diseases. Moreover, we explore the utilization of ketone body metabolism, including dietary interventions, in the context of aging, where mitochondrial dysfunction plays a crucial role. Through this review, we aim to present a comprehensive understanding of ketone body metabolism and its intricate relationship with mitochondrial function, spanning the potential implications in various health conditions and the aging process.
Topics: Humans; Cardiovascular Diseases; Ketone Bodies; 3-Hydroxybutyric Acid; Acetone; Non-alcoholic Fatty Liver Disease; Mitochondria
PubMed: 37766574
DOI: 10.5551/jat.RV22011 -
Metabolites Jun 2023Opposing evidence exists for the source of the hydrogen ions (H) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha...
Opposing evidence exists for the source of the hydrogen ions (H) during ketoacidosis. Organic and computational chemistry using dissociation constants and alpha equations for all pertinent ionizable metabolites were used to (1) document the atomic changes in the chemical reactions of ketogenesis and ketolysis and (2) identify the sources and quantify added fractional (~) H exchange (~He). All computations were performed for pH conditions spanning from 6.0 to 7.6. Summation of the ~He for given pH conditions for all substrates and products of each reaction of ketogenesis and ketolysis resulted in net reaction and pathway ~He coefficients, where negative revealed ~H release and positive revealed ~H uptake. Results revealed that for the liver (pH = 7.0), the net ~He for the reactions of ketogenesis ending in each of acetoacetate (AcAc), β-hydroxybutyrate (β-HB), and acetone were -0.9990, 0.0026, and 0.0000, respectively. During ketogenesis, ~H release was only evident for HMG CoA production, which is caused by hydrolysis and not ~H dissociation. Nevertheless, there is a net ~H release during ketogenesis, though this diminishes with greater proportionality of acetone production. For reactions of ketolysis in muscle (pH = 7.1) and brain (pH = 7.2), net ~H coefficients for β-HB and AcAc oxidation were -0.9649 and 0.0363 (muscle), and -0.9719 and 0.0291 (brain), respectively. The larger ~H release values for β-HB oxidation result from covalent ~H release during the oxidation-reduction. For combined ketogenesis and ketolysis, which would be the metabolic condition in vivo, the net ~H coefficient depends once again on the proportionality of the final ketone body product. For ketone body production in the liver, transference to blood, and oxidation in the brain and muscle for a ratio of 0.6:0.2:0.2 for β-HB:AcAc:acetone, the net ~He coefficients for liver ketogenesis, blood transfer, brain ketolysis, and net total (ketosis) equate to -0.1983, -0.0003, -0.2872, and -0.4858, respectively. The traditional theory of ketone bodies being metabolic acids causing systemic acidosis is incorrect. Summation of ketogenesis and ketolysis yield H coefficients that differ depending on the proportionality of ketone body production, though, in general, there is a small net H release during ketosis. Products formed during ketogenesis (HMG-CoA, acetoacetate, β-hydroxybutyrate) are created as negatively charged bases, not acids, and the final ketone body, acetone, does not have pH-dependent ionizable groups. Proton release or uptake during ketogenesis and ketolysis are predominantly caused by covalent modification, not acid dissociation/association. Ketosis (ketogenesis and ketolysis) results in a net fractional H release. The extent of this release is dependent on the final proportionality between acetoacetate, β-hydroxybutyrate, and acetone.
PubMed: 37512510
DOI: 10.3390/metabo13070803 -
Frontiers in Molecular Neuroscience 2023A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and... (Review)
Review
A growing body of evidence supports the beneficial effects of the ketone bodies (KBs), acetoacetate and β-hydroxybutyrate (BHB), on diverse physiological processes and diseases. Hence, KBs have been suggested as therapeutic tools for neurodegenerative diseases. KBs are an alternative fuel during fasting and starvation as they can be converted to Ac-CoA to produce ATP. A ketogenic diet (KD), enriched in fats and low in carbohydrates, induces KB production in the liver and favors their use in the brain. BHB is the most abundant KB in the circulation; in addition to its role as energy fuel, it exerts many actions that impact the set of proteins in the cell and tissue. BHB can covalently bind to proteins in lysine residues as a new post-translational modification (PTM) named β-hydroxybutyrylation (Kbhb). Kbhb has been identified in many proteins where Kbhb sites can be critical for binding to other proteins or cofactors. Kbhb is mostly found in proteins involved in chromatin structure, DNA repair, regulation of spliceosome, transcription, and oxidative phosphorylation. Histones are the most studied family of proteins with this PTM, and H3K9bhb is the best studied histone mark. Their target genes are mainly related to cell metabolism, chromatin remodeling and the control of circadian rhythms. The role of Kbhb on physiological processes is poorly known, but it might link KB metabolism to cell signaling and genome regulation. BHB also impacts the proteome by influencing proteostasis. This KB can modulate the Unfolded Protein Response (UPR) and autophagy, two processes involved in the maintenance of protein homeostasis through the clearance of accumulated unfolded and damaged proteins. BHB can support proteostasis and regulate the UPR to promote metabolism adaptation in the liver and prevent cell damage in the brain. Also, BHB stimulates autophagy aiding to the degradation of accumulated proteins. Protein aggregation is common to proteinopathies like Alzheimer's (AD) and Parkinson's (PD) diseases, where the KD and BHB treatment have shown favorable effects. In the present review, the current literature supporting the effects of KBs on proteome conformation and proteostasis is discussed, as well as its possible impact on AD and PD.
PubMed: 37575967
DOI: 10.3389/fnmol.2023.1214092 -
Reviews in Endocrine & Metabolic... Dec 2019Gut microbiota (GM) is a key contributor to host metabolism and physiology. Data generated on comparing diseased and healthy subjects have reported changes in the GM... (Review)
Review
Gut microbiota (GM) is a key contributor to host metabolism and physiology. Data generated on comparing diseased and healthy subjects have reported changes in the GM profile between both health states, suggesting certain bacterial composition could be involved in pathogenesis. Moreover, studies reported that reshaping of GM could contribute actively to disease recovery. Interestingly, ketogenic diets (KD) have emerged recently as new economic dietotherapeutic strategy to combat a myriad of diseases (refractory epilepsy, obesity, cancer, neurodegenerative diseases…). KD, understood in a broad sense, refers to whatever dietetic approximation, which causes physiological ketosis. Therefore, high fat-low carbs diets, fasting periods or caloric restriction constitute different strategies to produce an increase of main ketones bodies, acetoacetate and β-hydroxybutyrate, in blood. Involved biological mechanisms in ketotherapeutic effects are still to be unravelled. However, it has been pointed out that GM remodelling by KD, from now on "keto microbiota", may play a crucial role in patient response to KD treatment. In fact, germ-free animals were resistant to ketotherapeutic effects; reinforcing keto microbiota may be a powerful contributor to host disease recovery. In this review, we will comment the influence of gut microbiota on host, as well as, therapeutic potential of ketogenic diets and keto microbiota to restore health status. Current progress and limitations will be argued too. In spite of few studies have defined applicability and mechanisms of KD, in the light of results, keto microbiota might be a new useful therapeutic agent.
Topics: Animals; Diet, Ketogenic; Dysbiosis; Gastrointestinal Microbiome; Humans; Ketosis
PubMed: 31720986
DOI: 10.1007/s11154-019-09518-8 -
Neuropharmacology May 2018Although the mechanisms underlying the anti-seizure effects of the high-fat ketogenic diet (KD) remain unclear, a long-standing question has been whether ketone bodies... (Review)
Review
Although the mechanisms underlying the anti-seizure effects of the high-fat ketogenic diet (KD) remain unclear, a long-standing question has been whether ketone bodies (i.e., β-hydroxybutyrate, acetoacetate and acetone), either alone or in combination, contribute mechanistically. The traditional belief has been that while ketone bodies reflect enhanced fatty acid oxidation and a general shift toward intermediary metabolism, they are not likely to be the key mediators of the KD's clinical effects, as blood levels of β-hydroxybutyrate do not correlate consistently with improved seizure control. Against this unresolved backdrop, new data support ketone bodies as having anti-seizure actions. Specifically, β-hydroxybutyrate has been shown to interact with multiple novel molecular targets such as histone deacetylases, hydroxycarboxylic acid receptors on immune cells, and the NLRP3 inflammasome. Clearly, as a diet-based therapy is expected to render a broad array of biochemical, molecular, and cellular changes, no single mechanism can explain how the KD works. Specific metabolic substrates or enzymes are only a few of many important factors influenced by the KD that can collectively influence brain hyperexcitability and hypersynchrony. This review summarizes recent novel experimental findings supporting the anti-seizure and neuroprotective properties of ketone bodies.
Topics: Animals; Anticonvulsants; Diet, Ketogenic; Humans; Ketone Bodies; Seizures
PubMed: 29325899
DOI: 10.1016/j.neuropharm.2018.01.011