bims-kimdis 2024-08-11 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–08–11
eight papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.
Ketone bodies rescue T cell impairments induced by low glucose availability.
Impact of the ketogenic diet as a dietary approach on cardiovascular disease risk factors: a meta-analysis of randomized clinical trials.
Nrf2 as a regulator of energy metabolism and mitochondrial function.
FDA-approved disulfiram inhibits the NLRP3 inflammasome by regulating NLRP3 palmitoylation.
Pyroptosis leads to loss of centrosomal integrity in macrophages.
Near-infrared spectroscopy (NIRS) in vivo assessment of skeletal muscle oxidative capacity: a comparison of results from short versus long exercise protocols and reproducibility in non-athletic adults.
Effects of intensified training with insufficient recovery on joint level and single muscle fibre mechanical function: The role of myofibrillar Ca2+ sensitivity.

Cell Rep Med. 2024 Aug 01. pii: S2666-3791(24)00381-1. [Epub ahead of print] 101667

Ketogenic diet but not free-sugar restriction alters glucose tolerance, lipid metabolism, peripheral tissue phenotype, and gut microbiome: RCT.

Aaron Hengist, Russell G Davies, Jean-Philippe Walhin, Jariya Buniam, Lucy H Merrell, Lucy Rogers, Louise Bradshaw, Alfonso Moreno-Cabañas, Peter J Rogers, Jeff M Brunstrom, Leanne Hodson, Luc J C van Loon, Wiley Barton, Ciara O'Donovan, Fiona Crispie, Orla O'Sullivan, Paul D Cotter, Kathryn Proctor, James A Betts, Françoise Koumanov, Dylan Thompson, Javier T Gonzalez.

  Restricted sugar and ketogenic diets can alter energy balance/metabolism, but decreased energy intake may be compensated by reduced expenditure. In healthy adults, randomization to restricting free sugars or overall carbohydrates (ketogenic diet) for 12 weeks reduces fat mass without changing energy expenditure versus control. Free-sugar restriction minimally affects metabolism or gut microbiome but decreases low-density lipoprotein cholesterol (LDL-C). In contrast, a ketogenic diet decreases glucose tolerance, increases skeletal muscle PDK4, and reduces AMPK and GLUT4 levels. By week 4, the ketogenic diet reduces fasting glucose and increases apolipoprotein B, C-reactive protein, and postprandial glycerol concentrations. However, despite sustained ketosis, these effects are no longer apparent by week 12, when gut microbial beta diversity is altered, possibly reflective of longer-term adjustments to the ketogenic diet and/or energy balance. These data demonstrate that restricting free sugars or overall carbohydrates reduces energy intake without altering physical activity, but with divergent effects on glucose tolerance, lipoprotein profiles, and gut microbiome.

Keywords:  body fat; diet; energy balance; energy intake; ketogenic; lipoprotein; low carbohydrate; metabolism; physical activity; sugar

DOI:  https://doi.org/10.1016/j.xcrm.2024.101667
Eur J Nutr. 2024 Aug 06.

Ketone bodies rescue T cell impairments induced by low glucose availability.

Arianna Ferrari, Jessica Filoni, Carla Di Dedda, Lorenzo Piemonti, Paolo Monti.

   PURPOSE: Ketogenic diets are proposed as a therapeutic approach for type 1 and type 2 diabetes due to their low glucose intake. However, their potential effects on the immune system need investigation. This study aims to explore how glucose concentration and beta-hydroxybutyrate (BHB) impact T cell phenotype, metabolism, and function, with a focus on systemic inflammatory response (T2D) and autoimmunity (T1D).
METHODS: T cells from healthy donors were cultured in vitro under varying glucose concentrations with or without BHB. Flow cytometry was employed to analyze changes in T cell phenotype, while proliferation was evaluated through a CFSE dilution assay. Additionally, we used a novel flow cytometry method allowing a direct assessment of T cell metabolism.
RESULTS: Culturing T cells in low glucose concentrations revealed their dependency on glucose metabolism, leading to reduced proliferation rates, overexpression of exhaustion markers and increased susceptibility to Treg suppression and the influence of immune-modulating drugs such as rapamycin, FK506, and MMF. Notably, T cells cultured in low glucose concentrations increased the expression of BDH1 to utilize BHB as an alternative fuel source. Finally, the addition of BHB to the culture effectively rescued T cell impairments caused by insufficient glucose levels.
CONCLUSIONS: T cells display limited capacity to adapt to low glucose levels, resulting in profound functional impairment. However, T cell functions can be efficiently recovered by the presence of 2mM BHB.

Keywords:  Immunometabolism; Ketogenic diet; T cells; Type 1 diabetes

DOI:  https://doi.org/10.1007/s00394-024-03469-w
Am J Clin Nutr. 2024 Aug;pii: S0002-9165(24)00445-3. [Epub ahead of print]120(2): 294-309

Impact of the ketogenic diet as a dietary approach on cardiovascular disease risk factors: a meta-analysis of randomized clinical trials.

Zixuan Wang, Tu Chen, Sihai Wu, Xuesi Dong, Ming Zhang, Gaoxiang Ma.

   BACKGROUND: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, and the scarcity of scientific evidence regarding the impact of ketogenic diets on CVD risk factors necessitates urgent attention and redress.
OBJECTIVES: This meta-analysis evaluates the impact of the ketogenic diet on CVD risk factors compared with control diets through randomized controlled trials (RCTs).
METHODS: The study was registered in advance in the PROSPERO database (CRD42023491853). A systematic search was conducted across PubMed, Web of Science, EMBASE, and Cochrane Library to identify relevant RCTs. Fixed and random effects were employed to calculate the mean differences and 95% confidence intervals (CIs) for changes in CVD risk factors pre- and postketogenic diet intervention.
RESULTS: A total of 27 RCTs with 1278 participants were analyzed. The ketogenic diet intervention presented increase in total cholesterol (mean differences: 0.36 mmol/L; 95% CI: 0.15, 0.57; I2: 85.1%), low-density lipoprotein cholesterol (mean differences: 0.35 mmol/L; 95% CI: 0.20, 0.50; I2: 73.9%) and high-density lipoprotein cholesterol (mean differences: 0.16 mmol/L; 95% CI: 0.09, 0.23; I2: 86.7%) concentrations. Reductions were observed in the triglyceride (mean differences: -0.20 mmol/L; 95% CI: -0.29, -0.11; I2: 72.2%), blood glucose (mean differences: -0.18 mmol/L; 95% CI: -0.33, -0.02; I2: 76.4%), blood insulin (mean differences: -8.32 pmol/L; 95% CI: -14.52, -2.12; I2: 81.5%), diastolic blood pressure (mean differences: -1.41 mmHg; 95% CI: -2.57, -0.26; I2: 49.1%), weight (mean differences: -2.59 kg; 95% CI: -3.90, -1.28; I2: 87.4%), and body mass index (mean differences: -1.59 kg/m2; 95% CI: -2.32, -0.86; I2: 84.5%) concentrations after implementing ketogenic diets.
CONCLUSIONS: Although the ketogenic diet demonstrates benefits in terms of triglyceride, blood pressure, weight, and glycemic control, its impact on CVD risk factors, especially the elevated total cholesterol and low-density lipoprotein cholesterol concentrations, warrants a cautious approach.

Keywords:  cardiovascular disease; ketogenic diet; meta-analysis; randomized clinical trials; risk factors

DOI:  https://doi.org/10.1016/j.ajcnut.2024.04.021
FEBS Lett. 2024 Aug 08.

Nrf2 as a regulator of energy metabolism and mitochondrial function.

Alina Luchkova, Ana Mata, Susana Cadenas.

  Nuclear factor erythroid-2-related factor 2 (Nrf2) is essential for the control of cellular redox homeostasis. When activated, Nrf2 elicits cytoprotective effects through the expression of several genes encoding antioxidant and detoxifying enzymes. Nrf2 can also improve antioxidant defense via the pentose phosphate pathway by increasing NADPH availability to regenerate glutathione. Microarray and genome-wide localization analyses have identified many Nrf2 target genes beyond those linked to its redox-regulatory capacity. Nrf2 regulates several intermediary metabolic pathways and is involved in cancer cell metabolic reprogramming, contributing to malignant phenotypes. Nrf2 also modulates substrate utilization for mitochondrial respiration. Here we review the experimental evidence supporting the essential role of Nrf2 in the regulation of energy metabolism and mitochondrial function.

Keywords:  Nrf2; energy metabolism; metabolic reprogramming; mitochondria; oxidative stress; redox signaling

DOI:  https://doi.org/10.1002/1873-3468.14993
Cell Rep. 2024 Aug 07. pii: S2211-1247(24)00959-8. [Epub ahead of print]43(8): 114609

FDA-approved disulfiram inhibits the NLRP3 inflammasome by regulating NLRP3 palmitoylation.

Jie Xu, Joseph M Pickard, Gabriel Núñez.

  The NLRP3 inflammasome is dysregulated in autoinflammatory disorders caused by inherited mutations and contributes to the pathogenesis of several chronic inflammatory diseases. In this study, we discovered that disulfiram, a safe US Food and Drug Administration (FDA)-approved drug, specifically inhibits the NLRP3 inflammasome but not the NLRC4 or AIM2 inflammasomes. Disulfiram suppresses caspase-1 activation, ASC speck formation, and pyroptosis induced by several stimuli that activate NLRP3. Mechanistically, NLRP3 is palmitoylated at cysteine 126, a modification required for its localization to the trans-Golgi network and inflammasome activation, which was inhibited by disulfiram. Administration of disulfiram to animals inhibited the NLRP3, but not NLRC4, inflammasome in vivo. Our study uncovers a mechanism by which disulfiram targets NLRP3 and provides a rationale for using a safe FDA-approved drug for the treatment of NLRP3-associated inflammatory diseases.

Keywords:  CP: Immunology; NLRP3; disulfiram; gasdermin D; inflammasome; palmitoylation

DOI:  https://doi.org/10.1016/j.celrep.2024.114609
Cell Death Discov. 2024 Aug 08. 10(1): 354

Pyroptosis leads to loss of centrosomal integrity in macrophages.

Siyi Bai, Fatima Martin-Sanchez, David Brough, Gloria Lopez-Castejon.

NLRP3 forms a multiprotein inflammasome complex to initiate the inflammatory response when macrophages sense infection or tissue damage, which leads to caspase-1 activation, maturation and release of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 and Gasdermin-D (GSDMD) mediated pyroptosis. NLRP3 inflammasome activity must be controlled as unregulated and chronic inflammation underlies inflammatory and autoimmune diseases. Several findings uncovered that NLRP3 inflammasome activity is under the regulation of centrosome localized proteins such as NEK7 and HDAC6, however, whether the centrosome composition or structure is altered during the inflammasome activation is not known. Our data show that levels of the centrosomal scaffold protein pericentrin (PCNT) are reduced upon NLRP3 inflammasome activation via different activators in human and murine macrophages. PCNT loss occurs in the presence of membrane stabilizer punicalagin, suggesting this is not a consequence of membrane rupture. We found that PCNT loss is dependent on NLRP3 and active caspases as MCC950 and pan caspase inhibitor ZVAD prevent its degradation. Moreover, caspase-1 and GSDMD are both required for this NLRP3-mediated PCNT loss because absence of caspase-1 or GSDMD triggers an alternative regulation of PCNT via its cleavage by caspase-3 in response to nigericin stimulation. PCNT degradation occurs in response to nigericin, but also other NLRP3 activators including lysomotropic agent L-Leucyl-L-Leucine methyl ester (LLOMe) and hypotonicity but not AIM2 activation. Our work reveals that the NLRP3 inflammasome activation alters centrosome composition highlighting the need to further understand the role of this organelle during inflammatory responses.

DOI: https://doi.org/10.1038/s41420-024-02093-1
Front Physiol. 2024 ;15 1429673

Near-infrared spectroscopy (NIRS) in vivo assessment of skeletal muscle oxidative capacity: a comparison of results from short versus long exercise protocols and reproducibility in non-athletic adults.

Fistra J Tandirerung, Alexandra Jamieson, Elizabeth Hendrick, Alun D Hughes, Siana Jones.

   Background: Near-infrared spectroscopy (NIRS) provides a non-invasive, cost-effective method for assessing skeletal muscle oxidative capacity when combined with a short exercise protocol and arterial occlusions. However, the impact of different exercise protocols and reproducibility of the method in non-athletic adults have not previously been assessed.
Methods: Young, non-athletic adults (YA) were invited to perform a short duration, fast frequency contraction (SF) exercise protocol and a long duration slow frequency (LS) contraction protocol, combined with NIRS measurements and arterial occlusions to assess skeletal muscle oxidative capacity. YA and older non-athletic adults (OA; >65 years old) were invited to perform the SF exercise protocol twice to assess the reproducibility of this oxidative capacity measurement.
Results: We included 25 participants (14 male (56%), age range: 18-86 years) in the analyses. There was a strong positive correlation and good agreement between time constants derived following the SF and LS exercise protocols (Lin's concordance correlation coefficient: 0.69, p-value < 0.001 mean bias [LoA]: -3.2 [-31.0, 24.4] seconds. There was a strong positive correlation and good agreement between time constants derived from the SF exercise protocol in the YA & OA group (Lin's concordance correlation coefficient: 0.63, p-value < 0.001; mean bias [LoA] -6.4 [-34.0, 21.3] seconds).
Conclusion: These data provide evidence to suggest that NIRS is a reliable in vivo method for the assessment of skeletal muscle oxidative capacity irrespective of exercise protocol duration or muscle contraction frequency. NIRS-measured oxidative capacity via the SF exercise protocol was reproducible in non-athletic adults with a wide range in age.

Keywords:  exercise; exercise near-infrared spectroscopy; near-infrared spectroscopy; oxidative capacity; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2024.1429673
Appl Physiol Nutr Metab. 2024 Aug 09.

Effects of intensified training with insufficient recovery on joint level and single muscle fibre mechanical function: The role of myofibrillar Ca2+ sensitivity.

Olivia P Roussel, Christopher Pignanelli, Emma F Hubbard, Alexandra M Coates, Arthur Cheng, Jamie F Burr, Geoffrey Alonzo Power.

Intense exercise training with insufficient recovery time is associated with reductions in neuromuscular performance. However, it is unclear how single muscle fibre mechanical function and myofibrillar Ca2+ sensitivity contribute to these impairments. We investigated the effects of overload training on joint-level neuromuscular performance and cellular-level mechanical function. Fourteenathletes (4 female, 10 male) underwent a 3-week intensified training protocol consisting of up to 150% of their regular training hours with three additional high-intensity training sessions per week. Neuromuscular performance of the knee extensors was assessed via maximum voluntary contraction (MVC) force, electrically evoked twitch contractions, and a force-frequency relationship. Muscle biopsies were taken from the vastus lateralis to assess single fibre mechanical function. Neither MVC force nor twitch parameters were altered following training (all p>0.05), but a rightward shift in the force-frequency curve was observed with average reduction in force of 6-27% across frequencies 5-20Hz (all p<0.05). In single fibres, maximal force output was not reduced following training, but there was a rightward shift in the force-pCa curve driven by a 6% reduction in Ca2+ sensitivity (p<0.05). These data indicate intensified training leads to impaired Ca2+ sensitivity at the single fibre level, which in part explains impaired neuromuscular function at the joint level during lower frequencies of activation. This is an important consideration for athletes, as performance is often assessed at maximal levels of activation, and these underlying impairments in force generation may be less obvious.

DOI: https://doi.org/10.1139/apnm-2024-0189