bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2024‒01‒21
thirteen papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello
  1. Ketogenic diet and cardiovascular risk - state of the art review.
  2. Changes in the chronic and postprandial blood lipid profiles of trained competitive cyclists and triathletes following a ketogenic diet: a randomized crossover trial.
  3. Ketone Body Metabolism in Diabetic Kidney Disease.
  4. An 8-week ketogenic diet improves exercise endurance and liver antioxidant capacity after weight loss in obese mice.
  5. AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation.
  6. Global Energy Metabolism Deficit in Alzheimer Disease Brain.
  7. Cyclic fasting-mimicking diet plus bortezomib and rituximab is an effective treatment for chronic lymphocytic leukemia.
  8. The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.
  9. Muscle fibre mitochondrial [Ca2+ ] dynamics during Ca2+ waves in RYR1 gain-of-function mouse.
  10. NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
  11. NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis.
  12. Regulation of circadian rhythms by clock protein nuclear bodies.
  13. Impact of carbohydrate quantity and quality on maternal and pregnancy outcomes in gestational diabetes mellitus: A systematic review and meta-analysis.
  1. Curr Probl Cardiol. 2024 Jan 15. pii: S0146-2806(24)00041-0. [Epub ahead of print] 102402
    Ketogenic diet and cardiovascular risk - state of the art review.
    Joanna Popiolek-Kalisz.
      The ketogenic diet is based on extreme carbohydrate intake reduction and replacing the remaining with fat and has become a popular dietary pattern used for weight loss. The relationship between the ketogenic diet and cardiovascular risk is a controversial topic. This publication aimed to present evidence on the ketogenic diet and cardiovascular risk factors and mortality. The ketogenic diet does not fulfill the criteria of a healthy. It presents the potential for rapid short-term reduction of body mass, triglycerides level, Hb1Ac, and blood pressure. Its efficacy for weight loss and the above-mentioned metabolic changes is not significant in long-term observations. In terms of cardiovascular mortality, the low-carb pattern is more beneficial than very low-carbohydrate (including the ketogenic diet). There is still scarce evidence comparing ketogenic to the Mediterranean diet. Other safety concerns in cardiovascular patients such as adverse events related to ketosis, fat-free mass loss, or potential pharmacological interactions should be also taken into consideration in future research.
    Keywords:  cardiovascular prevention; cardiovascular risk; ketogenic diet; ketosis; very low carbohydrate high-fat diet
    DOI:  https://doi.org/10.1016/j.cpcardiol.2024.102402
  2. BMC Sports Sci Med Rehabil. 2024 Jan 16. 16(1): 19
    Changes in the chronic and postprandial blood lipid profiles of trained competitive cyclists and triathletes following a ketogenic diet: a randomized crossover trial.
    Austin J Graybeal, Andreas Kreutzer, Kamiah Moss, Meena Shah.
      BACKGROUND: The ketogenic diet (KD) is the most popular carbohydrate restriction strategy for endurance athletes. However, because the primary goal of employing the KD is to gain a competitive advantage in competition, endurance athletes may be less concerned with the influence of the KD on their cardiometabolic health; particularly their blood lipid profiles. Thus, the purpose of this study was to examine the chronic and postprandial blood lipid alterations following a two-week ad libitum KD compared to an ad libitum high-carbohydrate diet (HCD) and the athletes' habitual diet (HD) in a group of trained competitive cyclists and triathletes.METHODS: Six trained competitive cyclists and triathletes (female: 4, male: 2; age: 37.2 ± 12.2) completed this randomized crossover trial, which required them to follow a two-week ad libitum KD and HCD in a randomized order after their HD. Fasting blood lipids were collected following their HD and after two-weeks of the KD and HCD conditions. Postprandial blood lipid responses to a test meal reflective of the assigned diet were collected at the end of each diet condition.
    RESULTS: Fasting total cholesterol (TC) was significantly higher following the KD compared to the HD (p < 0.001) and HCD (p = 0.006). Postprandial incremental area under the curve for triglycerides (TRG), TRG:HDL ratio, and VLDL-C were significantly higher following the KD test meal compared to the HD (all p < 0.001) and HCD (all p = 0.001) test meals but LDL-C and LDL:HDL ratio were significantly lower following the KD compared to the HD and HCD test meals (all p < 0.001).
    CONCLUSIONS: Trained competitive cyclists and triathletes demonstrate increased TC in response to a two-week KD compared to a HCD or HD. Endurance athletes contemplating a KD should consider the potential for these blood lipid alterations, and future research should focus on postprandial blood lipid responses to determine if these changes manifest in chronic blood lipid shifts.
    TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04097171 (11 October 2019).
    Keywords:  Blood lipids; Cholesterol; Endurance athletes; High-carbohydrate diet; High-fat diets; Ketogenic diet; Low-carbohydrate diets
    DOI:  https://doi.org/10.1186/s13102-023-00801-5
  3. Kidney360. 2024 Jan 16.
    Ketone Body Metabolism in Diabetic Kidney Disease.
    Kosuke Yamahara, Mako Yasuda-Yamahara, Shogo Kuwagata, Masami Chin-Kanasaki, Shinji Kume.
      Ketone bodies have a negative image because of ketoacidosis, one of the acute and serious complications in diabetes. The negative image persists despite the fact that ketone bodies are physiologically produced in the liver and serve as an indispensable energy source in extrahepatic organs, particularly during long-term fasting. However, accumulating experimental evidence suggests that ketone bodies exert various health benefits. Particularly in the field of aging research, there is growing interest in the potential organoprotective effects of ketone bodies. In addition, ketone bodies have a potential role in preventing kidney diseases including diabetic kidney disease (DKD), a diabetic complication caused by prolonged hyperglycemia that leads to a decline in kidney function. Ketone bodies may help alleviate the renal burden from hyperglycemia by being utilized as an alternative energy source in diabetic patients. Furthermore, ketone body production may reduce inflammation and delay the progression of several kidney diseases in addition to DKD. Although there is still insufficient research on the use of ketone bodies as a treatment and their effects, their renoprotective effects are being gradually proven. This review outlines the ketone body-mediated renoprotective effects in DKD and other kidney diseases.
    DOI:  https://doi.org/10.34067/KID.0000000000000359
  4. Front Nutr. 2023 ;10 1322936
    An 8-week ketogenic diet improves exercise endurance and liver antioxidant capacity after weight loss in obese mice.
    Ying Wang, Yunlong Dong, Ying Zhang, Jiabao Yan, Cuiru Ren, Hong Ma, Zhenwei Cui.
      Evolving evidence supports the role of the ketogenic diet (KD) in weight loss. However, no coherent conclusions are drawn on its impact on the effect of KD on exercise and antioxidant capacity after weight loss in obese individuals. We evaluated the exercise performance, energy metabolism and antioxidant capacity of mice after weight loss using high-fat diet-induced obese mice, and used KD and normal diet (ND) intervention, respectively, to provide a theoretical basis for further study of the health effects of KD. Our results showed that the 8-week KD significantly reduced the body weight of obese mice and improved the performance of treadmill exercise, but had no significant effect on grip strength. Serum biochemical results suggest that KD has the risk of elevating blood lipid. In liver tissue, KD significantly reduced the level of oxidative stress and increased the antioxidant capacity of the liver. Our findings suggest that the intervention with KD led to weight loss, modulate energy metabolism and improve aerobic exercise endurance in obese mice. Despite its antioxidant potential in the liver, the utilization of KD still requires caution. This study underscores the need for further investigation into the health impacts of KD, especially in regard to its potential risks.
    Keywords:  exercise performance; ketogenic diet; obesity; oxidation resistance; oxidative stress
    DOI:  https://doi.org/10.3389/fnut.2023.1322936
  5. Sci Rep. 2024 Jan 19. 14(1): 1713
    AMPKα2 regulates fasting-induced hyperketonemia by suppressing SCOT ubiquitination and degradation.
    Lingxue Zhang, Yanqiao Lu, Junqing An, Yin Wu, Zhixue Liu, Ming-Hui Zou.
      Ketone bodies serve as an energy source, especially in the absence of carbohydrates or in the extended exercise. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a crucial energy sensor that regulates lipid and glucose metabolism. However, whether AMPK regulates ketone metabolism in whole body is unclear even though AMPK regulates ketogenesis in liver. Prolonged resulted in a significant increase in blood and urine levels of ketone bodies in wild-type (WT) mice. Interestingly, fasting AMPKα2-/- and AMPKα1-/- mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. BHB tolerance assays revealed that both AMPKα2-/- and AMPKα1-/- mice exhibited slower ketone consumption compared to WT mice, as indicated by higher blood BHB or urine BHB levels in the AMPKα2-/- and AMPKα1-/- mice even after the peak. Interestingly, fasting AMPKα2-/- and AMPKα1-/- mice exhibited significantly higher levels of ketone bodies in both blood and urine compared to fasting WT mice. . Specifically, AMPKα2ΔMusc mice showed approximately a twofold increase in blood BHB levels, and AMPKα2ΔMyo mice exhibited a 1.5-fold increase compared to their WT littermates after a 48-h fasting. However, blood BHB levels in AMPKα1ΔMusc and AMPKα1ΔMyo mice were as same as in WT mice. Notably, AMPKα2ΔMusc mice demonstrated a slower rate of BHB consumption in the BHB tolerance assay, whereas AMPKα1ΔMusc mice did not show such an effect. Declining rates of body weights and blood glucoses were similar among all the mice. Protein levels of SCOT, the rate-limiting enzyme of ketolysis, decreased in skeletal muscle of AMPKα2-/- mice. Moreover, SCOT protein ubiquitination increased in C2C12 cells either transfected with kinase-dead AMPKα2 or subjected to AMPKα2 inhibition. AMPKα2 physiologically binds and stabilizes SCOT, which is dependent on AMPKα2 activity.
    DOI:  https://doi.org/10.1038/s41598-023-49991-5
  6. J Prev Alzheimers Dis. 2024 ;11(1): 171-178
    Global Energy Metabolism Deficit in Alzheimer Disease Brain.
    V Patel, J Mill, O C Okonkwo, S Salamat, L Li, T Raife.
      BACKGROUND: The understanding of Alzheimer's disease (AD) has been dominated by the amyloid hypothesis. However, therapies targeting beta-amyloid have largely failed, generating interest in other potential pathogenic factors including energy metabolism.OBJECTIVES: To interrogate canonical energy metabolism pathways from human prefrontal cortical tissue samples obtained from necropsy comparing AD and control.
    DESIGN, SETTING, AND PARTICIPANTS: Postmortem pre-frontal cortical tissue from 10 subjects histologically diagnosed with AD and 10 control (CTRL) subjects was subjected to untargeted metabolomics to interrogate energy metabolism pathways. The samples were matched by age, sex, and post-mortem interval. Metabolite Measurements: Untargeted metabolomics analyses were via Metabolon®.
    RESULTS: Glucose-derived energy metabolites in the glycolytic and pentose phosphate pathway and the ketone body β-hydroxybutyrate were uniformly decreased in AD brain vs. CTRL brain.
    CONCLUSION: This pilot study aimed to identify energy metabolism abnormalities using untargeted brain metabolomics in two independent subject cohorts. Our study revealed a pattern of global energy deficit in AD brain, supporting a growing body of evidence of deficient energy metabolism in AD.
    Keywords:  Alzheimer disease; beta-hydroxybutyrate; energy metabolism deficits; ketone body; metabolomics
    DOI:  https://doi.org/10.14283/jpad.2023.91
  7. Cancer Res. 2024 Jan 19.
    Cyclic fasting-mimicking diet plus bortezomib and rituximab is an effective treatment for chronic lymphocytic leukemia.
    Franca Raucci, Claudio Vernieri, Maira Di Tano, Francesca Ligorio, Olga Blaževitš, Samuel Lazzeri, Anastasiya Shmahala, Giuseppe Fragale, Giulia Salvadori, Gabriele Varano, Stefano Casola, Roberta Buono, Euplio Visco, Filippo de Braud, Valter D Longo.
      Cyclic fasting-mimicking diet (FMD) is an experimental nutritional intervention with potent antitumor activity in preclinical models of solid malignancies. FMD cycles are also safe and active metabolically and immunologically in cancer patients. Here, we reported on the outcome of FMD cycles in two chronic lymphocytic leukemia (CLL) patients and investigated the effects of fasting and FMD cycles in pre-clinical CLL models. Fasting mimicking conditions in murine CLL models had mild cytotoxic effects, which resulted in apoptosis activation mediated in part by lowered insulin and IGF-1 concentrations. In CLL cells, fasting conditions promoted an increase in proteasome activity that served as a starvation escape pathway. Pharmacological inhibition of this escape mechanism with the proteasome inhibitor bortezomib (BTZ) resulted in a strong enhancement of the pro-apoptotic effects of starvation conditions in vitro. In mouse CLL models, combining cyclic fasting/FMD with BTZ and rituximab (RTX), an anti-CD20 antibody, delayed CLL progression and resulted in significant prolongation of mouse survival. Overall, the effect of proteasome inhibition in combination with FMD cycles in promoting CLL death supports the targeting of starvation escape pathways as an effective treatment strategy that should be tested in clinical trials.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-23-0295
  8. Cell Death Dis. 2024 Jan 17. 15(1): 58
    The mitochondrial ATP-dependent potassium channel (mitoKATP) controls skeletal muscle structure and function.
    Giulia Di Marco, Gaia Gherardi, Agnese De Mario, Ilaria Piazza, Martina Baraldo, Andrea Mattarei, Bert Blaauw, Rosario Rizzuto, Diego De Stefani, Cristina Mammucari.
      MitoKATP is a channel of the inner mitochondrial membrane that controls mitochondrial K+ influx according to ATP availability. Recently, the genes encoding the pore-forming (MITOK) and the regulatory ATP-sensitive (MITOSUR) subunits of mitoKATP were identified, allowing the genetic manipulation of the channel. Here, we analyzed the role of mitoKATP in determining skeletal muscle structure and activity. Mitok-/- muscles were characterized by mitochondrial cristae remodeling and defective oxidative metabolism, with consequent impairment of exercise performance and altered response to damaging muscle contractions. On the other hand, constitutive mitochondrial K+ influx by MITOK overexpression in the skeletal muscle triggered overt mitochondrial dysfunction and energy default, increased protein polyubiquitination, aberrant autophagy flux, and induction of a stress response program. MITOK overexpressing muscles were therefore severely atrophic. Thus, the proper modulation of mitoKATP activity is required for the maintenance of skeletal muscle homeostasis and function.
    DOI:  https://doi.org/10.1038/s41419-024-06426-x
  9. Acta Physiol (Oxf). 2024 Jan 19. e14098
    Muscle fibre mitochondrial [Ca2+ ] dynamics during Ca2+ waves in RYR1 gain-of-function mouse.
    Rhayanna B Gaglianone, Bradley S Launikonis.
      AIM: A fraction of the Ca2+ released from the sarcoplasmic reticulum (SR) enters mitochondria to transiently increase its [Ca2+ ] ([Ca2+ ]mito ). This transient [Ca2+ ]mito increase may be important in the resynthesis of ATP and other processes. The resynthesis of ATP in the mitochondria generates heat that can lead to hypermetabolic reactions in muscle with ryanodine receptor 1 (RyR1) variants during the cyclic releasing of SR Ca2+ in the presence of a RyR1 agonist. We aimed to analyse whether the mitochondria of RYR1 variant muscle handles Ca2+ differently from healthy muscle.METHODS: We used confocal microscopy to track mitochondrial and cytoplasmic Ca2+ with fluorescent dyes simultaneously during caffeine-induced Ca2+ waves in extensor digitorum longus muscle fibres from healthy mice and mice heterozygous (HET) for a malignant hyperthermia-causative RYR1 variant.
    RESULTS: Mitochondrial Ca2+ -transient peaks trailed the peak of cytoplasmic Ca2+ transients by many seconds with [Ca2+ ]mito not increasing by more than 250 nM. A strong linear relationship between cytoplasmic Ca2+ and [Ca2+ ]mito amplitudes was observed in HET RYR1 KI fibres but not wild type (WT).
    CONCLUSION: Our results indicate that [Ca2+ ]mito change within the nM range during SR Ca2+ release. HET fibre mitochondria are more sensitive to SR Ca2+ release flux than WT. This may indicate post-translation modification differences of the mitochondrial Ca2+ uniporter between the genotypes.
    Keywords:  Ca2+; confocal; malignant hyperthermia; mitochondria; ryanodine receptor; skeletal muscle
    DOI:  https://doi.org/10.1111/apha.14098
  10. J Cell Biochem. 2024 Jan 15.
    NAD+ supplementation prevents STING-induced senescence in CD8+ T cells by improving mitochondrial homeostasis.
    Bin Ye, Yingting Pei, Lujing Wang, Dehao Meng, Yu Zhang, Shuang Zou, Henian Li, Jinying Liu, Ziying Xie, Changhong Tian, Yuqi Jiang, Yu Qiao, Xu Gao, Yanfen Zhang, Ning Ma.
      Understanding the connection between senescence phenotypes and mitochondrial dysfunction is crucial in aging and premature aging diseases. Loss of mitochondrial function leads to a decline in T cell function, which plays a significant role in this process. However, more research is required to determine if improving mitochondrial homeostasis alleviates senescence phenotypes. Our research has shown an association between NAD+ and senescent T cells through the cGAS-STING pathway, which can lead to an inflammatory phenotype. Further research is needed to fully understand the role of NAD+ in T-cell aging and how it can be utilized to improve mitochondrial homeostasis and alleviate senescence phenotypes. We demonstrate here that mitochondrial dysfunction and cellular senescence with a senescence-associated secretory phenotype (SASP) occur in senescent T cells and tumor-bearing mice. Senescence is mediated by a stimulator of interferon genes (STING) and involves ectopic cytoplasmic DNA. We further show that boosting intracellular NAD+ levels with nicotinamide mononucleotide (NMN) prevents senescence and SASP by promoting mitophagy. NMN treatment also suppresses senescence and neuroinflammation and improves the survival cycle of mice. Encouraging mitophagy may be a useful strategy to prevent CD8+ T cells from senescence due to mitochondrial dysfunction. Additionally, supplementing with NMN to increase NAD+ levels could enhance survival rates in mice while also reducing senescence and inflammation, and enhancing mitophagy as a potential therapeutic intervention.
    Keywords:  SASP; cGAS-STING; mitochondria; nicotinamide mononucleotide; senescence
    DOI:  https://doi.org/10.1002/jcb.30522
  11. Int J Mol Med. 2024 Mar;pii: 25. [Epub ahead of print]53(3):
    NLRP3 inflammasome mediates abnormal epithelial regeneration and distal lung remodeling in silica‑induced lung fibrosis.
    Hong Zhou, Qun Zhang, Chenyang Liu, Jiahao Fan, Wen Huang, Nan Li, Mingxia Yang, Hong Wang, Weiping Xie, Hui Kong.
      NOD-like receptor protein 3 (NLRP3) inflammasome is closely related to silica particle‑induced chronic lung inflammation but its role in epithelial remodeling, repair and regeneration in the distal lung during development of silicosis remains to be elucidated. The present study aimed to determine the effects of the NLRP3 inflammasome on epithelial remodeling and cellular regeneration and potential mechanisms in the distal lung of silica‑treated mice at three time points. Pulmonary function assessment, inflammatory cell counting, enzyme‑linked immunosorbent assay, histological and immunological analyses, hydroxyproline assay and western blotting were used in the study. Single intratracheal instillation of a silica suspension caused sustained NLRP3 inflammasome activation in the distal lung. Moreover, a time‑dependent increase in airway resistance and a decrease in lung compliance accompanied progression of pulmonary fibrosis. In the terminal bronchiole, lung remodeling including pyroptosis (membrane‑distributed GSDMD+), excessive proliferation (Ki67+), mucus overproduction (mucin 5 subtype AC and B) and epithelial‑mesenchymal transition (decreased E‑Cadherin+ and increased Vimentin+), was observed by immunofluorescence analysis. Notably, aberrant spatiotemporal expression of the embryonic lung stem/progenitor cell markers SOX2 and SOX9 and ectopic distribution of bronchioalveolar stem cells were observed in the distal lung only on the 7th day after silica instillation (the early inflammatory phase of silicosis). Western blotting revealed that the Sonic hedgehog/Glioma‑associated oncogene (Shh/Gli) and Wnt/β‑catenin pathways were involved in NLRP3 inflammasome activation‑mediated epithelial remodeling and dysregulated regeneration during the inflammatory and fibrotic phases. Overall, sustained NLRP3 inflammasome activation led to epithelial remodeling in the distal lung of mice. Moreover, understanding the spatiotemporal profile of dysregulated epithelial repair and regeneration may provide a novel therapeutic strategy for inhalable particle‑related chronic inflammatory and fibrotic lung disease.
    Keywords:  NLRP3 inflammasome; bronchioalveolar stem cell; bronchoalveolar duct junction; lung remodeling; regeneration; repair
    DOI:  https://doi.org/10.3892/ijmm.2024.5349
  12. Proc Natl Acad Sci U S A. 2024 Jan 30. 121(5): e2321334121
    Regulation of circadian rhythms by clock protein nuclear bodies.
    Ye Yuan, Swathi Yadlapalli.
      
    DOI:  https://doi.org/10.1073/pnas.2321334121
  13. Diabetes Metab Syndr. 2024 Jan 04. pii: S1871-4021(24)00002-X. [Epub ahead of print]18(1): 102941
    Impact of carbohydrate quantity and quality on maternal and pregnancy outcomes in gestational diabetes mellitus: A systematic review and meta-analysis.
    Martin Ming Him Wong, Mandy Yuen-Man Chan, Tsoi Pan Ng, Jimmy Chun Yu Louie.
      OBJECTIVE: To evaluate the impact of carbohydrate quantity and quality on maternal and pregnancy outcomes in gestational diabetes mellitus.METHODS: Using a pre-defined search strategy, two researchers systematically searched MEDLINE, CINAHL Plus, and PubMed for randomized controlled trials comparing low-carbohydrate, low-glycaemic index, or low-glycaemic load diets with usual care in gestational diabetes mellitus. Mean differences and risk ratios were extracted.
    RESULTS: Thirteen studies with 877 participants were included. Low-carbohydrate diet did not significantly differ from usual care for fasting blood glucose (3 studies; mean difference: 1.60 mmol/L; 95 % confidence interval: -1.95, 5.15), insulin requirement (2 studies; risk ratio: 1.01; 95 % confidence interval: 0.31, 3.05), birthweight (4 studies; mean difference: -0.23 kg; 95 % confidence interval: -1.90, 1.45), caesarean delivery (5 studies; risk ratio: 1.11; 95 % confidence interval: 0.66, 1.85), macrosomia (3 studies; risk ratio: 0.35; 95 % confidence interval: 0.00, 2130.64), large-for-gestational-age (2 studies; risk ratio: 0.46; 95 % confidence interval: 0.03, 7.20), and small-for-gestational-age infants (2 studies; risk ratio: 0.94; 95 % confidence interval: 0.00, 231.18). Low-glycaemic index diet did not significantly differ from usual care for the above outcomes either. However, low-glycaemic load diet reduced macrosomia risk (2 studies; risk ratio: 0.51; 95 % confidence interval: 0.43, 0.59).
    CONCLUSIONS: Low-carbohydrate and low-glycaemic index diets do not differ from usual care for most maternal and foetal outcomes in gestational diabetes mellitus. But low-glycaemic load diet may reduce macrosomia risk.
    Keywords:  Carbohydrate quality; Carbohydrate quantity; Gestational diabetes; Glycaemic index; Glycaemic load
    DOI:  https://doi.org/10.1016/j.dsx.2024.102941
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