bims-kimdis 2024-06-16 papers

bims-kimdis

Biomed News

on Ketones, inflammation and mitochondria in disease

Issue of 2024–06–16
ten papers selected by
Matías Javier Monsalves Álvarez, Universidad Andrés Bello

A Ketone Monoester with Carbohydrate Improves Cognitive Measures Postexercise, but Not Performance in Trained Females - Erratum.
Discovery of periplasmic solute binding proteins with specificity for ketone bodies: β-hydroxybutyrate binding proteins.
Hepatic ketogenesis is not required for starvation adaptation in mice.
The impact of carbohydrate restriction-induced elevations in low-density lipoprotein cholesterol on progression of coronary atherosclerosis: the ketogenic diet trial study design.
A Natural Metabolite and Inhibitor of the NLRP3 Inflammasome: 4-hydroxynonenal.
More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα.
ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.
Inflammasome-independent pyroptosis.
Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights.
Regulation of metabolism by circadian rhythms: Support from time-restricted eating, intestinal microbiota & omics analysis.

Med Sci Sports Exerc. 2024 Jul 01. 56(7): 1345-1346

A Ketone Monoester with Carbohydrate Improves Cognitive Measures Postexercise, but Not Performance in Trained Females - Erratum.

DOI: https://doi.org/10.1249/MSS.0000000000003461
Protein Sci. 2024 Jul;33(7): e5025

Discovery of periplasmic solute binding proteins with specificity for ketone bodies: β-hydroxybutyrate binding proteins.

Bryant J Kane, Junko Okuda-Shimazaki, Madelyn M Andrews, Joseph A Kerrigan, Kyle V Murphy, Koji Sode.

  Polyhydroxyalkanoates are a class of biodegradable, thermoplastic polymers which represent a major carbon source for various bacteria. Proteins which mediate the translocation of polyhydroxyalkanoate breakdown products, such as β-hydroxybutyrate (BHB)-a ketone body which in humans serves as an important biomarker, have not been well characterized. In our investigation to screen a solute-binding protein (SBP) which can act as a suitable recognition element for BHB, we uncovered insights at the intersection of bacterial metabolism and diagnostics. Herein, we identify SBPs associated with putative ATP-binding cassette transporters that specifically recognize BHB, with the potential to serve as recognition elements for continuous quantification of this analyte. Through bioinformatic analysis, we identified candidate SBPs from known metabolizers of polyhydroxybutyrate-including proteins from Cupriavidus necator, Ensifer meliloti, Paucimonas lemoignei, and Thermus thermophilus. After recombinant expression in Escherichia coli, we demonstrated with intrinsic tryptophan fluorescence spectroscopy that four candidate proteins interacted with BHB, ranging from nanomolar to micromolar affinity. Tt.2, an intrinsically thermostable protein from Thermus thermophilus, was observed to have the tightest binding and specificity for BHB, which was confirmed by isothermal calorimetry. Structural analyses facilitated by AlphaFold2, along with molecular docking and dynamics simulations, were used to hypothesize key residues in the binding pocket and to model the conformational dynamics of substrate unbinding. Overall, this study provides strong evidence identifying the cognate ligands of SBPs which we hypothesize to be involved in prokaryotic cellular translocation of polyhydroxyalkanoate breakdown products, while highlighting these proteins' promising biotechnological application.

Keywords:  AlphaFold2; molecular dynamics; molecular recognition; periplasmic binding protein; poly(hydroxyalkanoate); solute binding protein; β‐hydroxybutyrate

DOI:  https://doi.org/10.1002/pro.5025
Mol Metab. 2024 Jun 12. pii: S2212-8778(24)00098-X. [Epub ahead of print] 101967

Hepatic ketogenesis is not required for starvation adaptation in mice.

Kyle Feola, Andrea H Venable, Tatyana Broomfield, Morgan Villegas, Xiaorong Fu, Shawn Burgess, Sarah C Huen.

   OBJECTIVE: In response to bacterial inflammation, anorexia of acute illness is protective and is associated with the induction of fasting metabolic programs such as ketogenesis. Forced feeding during the anorectic period induced by bacterial inflammation is associated with suppressed ketogenesis and increased mortality. As ketogenesis is considered essential in fasting adaptation, we sought to determine the role of ketogenesis in illness-induced anorexia.
METHODS: A mouse model of inducible hepatic specific deletion of the rate limiting enzyme for ketogenesis (HMG-CoA synthase 2, Hmgcs2) was used to investigate the role of ketogenesis in endotoxemia, a model of bacterial inflammation, and in prolonged starvation.
RESULTS: Mice deficient of hepatic Hmgcs2 failed to develop ketosis during endotoxemia and during prolonged fasting. Surprisingly, hepatic HMGCS2 deficiency and the lack of ketosis did not affect survival, glycemia, or body temperature in response to endotoxemia. Mice with hepatic ketogenic deficiency also did not exhibit any defects in starvation adaptation and were able to maintain blood glucose, body temperature, and lean mass compared to littermate wild-type controls. Mice with hepatic HMGCS2 deficiency exhibited higher levels of plasma acetate levels in response to fasting.
CONCLUSIONS: Circulating hepatic-derived ketones do not provide protection against endotoxemia, suggesting that alternative mechanisms drive the increased mortality from forced feeding during illness-induced anorexia. Hepatic ketones are also dispensable for surviving prolonged starvation in the absence of inflammation. Our study challenges the notion that hepatic ketogenesis is required to maintain blood glucose and preserve lean mass during starvation, raising the possibility of extrahepatic ketogenesis and use of alternative fuels as potential means of metabolic compensation.

Keywords:  HMGCS2; endotoxemia; fasting metabolism; ketogenesis; starvation adaptation

DOI:  https://doi.org/10.1016/j.molmet.2024.101967
Coron Artery Dis. 2024 Jun 11.

The impact of carbohydrate restriction-induced elevations in low-density lipoprotein cholesterol on progression of coronary atherosclerosis: the ketogenic diet trial study design.

Denise Alison R Javier, Venkat S Manubolu, Nicholas G Norwitz, April Kinninger, Jairo Aldana-Bitar, Ahmed Ghanem, Khadije Ahmad, Will D Vicuna, Hossein Hamidi, Marziyeh Bagheri, Tasneem Elsayed, Bea Villanueva, Keishi Ichikawa, Ferdinand Flores, Sajad Hamal, David Feldman, Matthew J Budoff.

BACKGROUND: Despite innovations in pharmacotherapy to lower lipoprotein cholesterol and apolipoprotein B, risk factors for atherosclerotic cardiovascular disease (ASCVD), ASCVD persists as the leading global cause of mortality. Elevations in low-density lipoprotein cholesterol (LDL-C) are a well-known risk factor and have been a main target in the treatment of ASCVD. The latest research suggests that ketogenic diets are effective at improving most non-LDL-C/apolipoprotein B cardiometabolic risk factors. However, ketogenic diets can induce large increases in LDL-C to >190 mg/dl in some individuals. Interestingly, these individuals are often otherwise lean and healthy. The influence of increased levels of LDL-C resulting from a carbohydrate-restricted ketogenic diet on the progression of atherosclerosis in otherwise metabolically healthy individuals is poorly understood. This observational study aims to assess and describe the progression of coronary atherosclerosis in this population within 12 months.
METHODS: Hundred relatively lean individuals who adopted ketogenic diets and subsequently exhibited hypercholesterolemia with LDL-C to >190 mg/dl, in association with otherwise good metabolic health markers, were enrolled and observed over a period of 12 months. Participants underwent serial coronary computed tomography angiography scans to assess the progression of coronary atherosclerosis in a year.
RESULTS: Data analysis shall begin following the conclusion of the trial with results to follow.
CONCLUSION: Ketogenic diets have generated debate and raised concerns within the medical community, especially in the subset exhibiting immense elevations in LDL-C, who interestingly are lean and healthy. The relationship between elevated LDL-C and ASCVD progression in this population will provide better insight into the effects of diet-induced hypercholesterolemia.

DOI: https://doi.org/10.1097/MCA.0000000000001395
J Cell Immunol. 2024 ;6(2): 76-81

A Natural Metabolite and Inhibitor of the NLRP3 Inflammasome: 4-hydroxynonenal.

Jinmin Zhang, Bradford C Berk, Chia George Hsu.

  The NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome, crucial in the innate immune response, is linked to various human diseases. However, the effect of endogenous metabolites, like 4-hydroxynonenal (HNE), on NLRP3 inflammasome activity remains underexplored. Recent research highlights HNE's inhibitory role in NLRP3 inflammasome activation, shedding light on its potential as an endogenous regulator of inflammatory responses. Studies demonstrate that HNE blocks NLRP3 inflammasome-mediated pyroptosis and IL-1β secretion. Additionally, covalent targeting emerges as a common mechanism for inhibiting NLRP3 inflammasome assembly, offering promising avenues for therapeutic intervention. Further investigation is needed to understand the impact of endogenous HNE on NLRP3 inflammasome activation, especially in settings where lipid peroxidation byproducts like HNE are produced. Understanding the intricate interplay between HNE and the NLRP3 inflammasome holds significant potential for unraveling novel therapeutic strategies for inflammatory disorders.

Keywords:  4-hydroxynonenal; Inflammation; Macrophage; NLRP3; Pyroptosis

DOI:  https://doi.org/10.33696/immunology.6.192
J Physiol. 2024 Jun 08.

More than the clock: distinct regulation of muscle function and metabolism by PER2 and RORα.

Shivani Mansingh, Geraldine Maier, Julien Delezie, Pål O Westermark, Danilo Ritz, Wandrille Duchemin, Gesa Santos, Bettina Karrer-Cardel, Stefan A Steurer, Urs Albrecht, Christoph Handschin.

  Circadian rhythms, governed by the dominant central clock, in addition to various peripheral clocks, regulate almost all biological processes, including sleep-wake cycles, hormone secretion and metabolism. In certain contexts, the regulation and function of the peripheral oscillations can be decoupled from the central clock. However, the specific mechanisms underlying muscle-intrinsic clock-dependent modulation of muscle function and metabolism remain unclear. We investigated the outcome of perturbations of the primary and secondary feedback loops of the molecular clock in skeletal muscle by specific gene ablation of Period circadian regulator 2 (Per2) and RAR-related orphan receptor alpha (Rorα), respectively. In both models, a dampening of core clock gene oscillation was observed, while the phase was preserved. Moreover, both loops seem to be involved in the homeostasis of amine groups. Highly divergent outcomes were seen for overall muscle gene expression, primarily affecting circadian rhythmicity in the PER2 knockouts and non-oscillating genes in the RORα knockouts, leading to distinct outcomes in terms of metabolome and phenotype. These results highlight the entanglement of the molecular clock and muscle plasticity and allude to specific functions of different clock components, i.e. the primary and secondary feedback loops, in this context. The reciprocal interaction between muscle contractility and circadian clocks might therefore be instrumental to determining a finely tuned adaptation of muscle tissue to perturbations in health and disease. KEY POINTS: Specific perturbations of the primary and secondary feedback loop of the molecular clock result in specific outcomes on muscle metabolism and function. Ablation of Per2 (primary loop) or Rorα (secondary loop) blunts the amplitude of core clock genes, in absence of a shift in phase. Perturbation of the primary feedback loop by deletion of PER2 primarily affects muscle gene oscillation. Knockout of RORα and the ensuing modulation of the secondary loop results in the aberrant expression of a large number of non-clock genes and proteins. The deletion of PER2 and RORα affects muscle metabolism and contractile function in a circadian manner, highlighting the central role of the molecular clock in modulating muscle plasticity.

Keywords:  PER2; RORα; circadian rhythm; exercise; metabolism; molecular clock; skeletal muscle; transcriptional regulation

DOI:  https://doi.org/10.1113/JP285585
Cell Death Dis. 2024 Jun 11. 15(6): 407

ER-mitochondria association negatively affects wound healing by regulating NLRP3 activation.

Caterina Licini, Gianluca Morroni, Guendalina Lucarini, Veronica Angela Maria Vitto, Fiorenza Orlando, Sonia Missiroli, Gloria D'Achille, Mariasole Perrone, Tatiana Spadoni, Laura Graciotti, Giorgia Bigossi, Mauro Provinciali, Annamaria Offidani, Monica Mattioli-Belmonte, Oscar Cirioni, Paolo Pinton, Oriana Simonetti, Saverio Marchi.

Methicillin-resistant Staphylococcus aureus (MRSA) is the most common causative agent of acute bacterial skin and skin-structure infections (ABSSSI), one of the major challenges to the health system worldwide. Although the use of antibiotics as the first line of intervention for MRSA-infected wounds is recommended, important side effects could occur, including cytotoxicity or immune dysregulation, thus affecting the repair process. Here, we show that the oxazolidinone antibiotic linezolid (LZD) impairs wound healing by aberrantly increasing interleukin 1 β (IL-1β) production in keratinocytes. Mechanistically, LZD triggers a reactive oxygen species (ROS)-independent mitochondrial damage that culminates in increased tethering between the endoplasmic reticulum (ER) and mitochondria, which in turn activates the NLR family pyrin domain-containing 3 (NLRP3) inflammasome complex by promoting its assembly to the mitochondrial surface. Downregulation of ER-mitochondria contact formation is sufficient to inhibit the LZD-driven NLRP3 inflammasome activation and IL-1β production, restoring wound closure. These results identify the ER-mitochondria association as a key factor for NLRP3 activation and reveal a new mechanism in the regulation of the wound healing process that might be clinically relevant.

DOI: https://doi.org/10.1038/s41419-024-06765-9
Curr Opin Immunol. 2024 Jun 13. pii: S0952-7915(24)00022-0. [Epub ahead of print]88 102432

Inflammasome-independent pyroptosis.

Xing Liu, Judy Lieberman.

Gasdermins are membrane pore-forming proteins that cause pyroptosis, an inflammatory cell death in which cells burst and release cytokines, chemokines, and other host alarm signals, such as ATP and HMGB1, which recruit and activate immune cells at sites of infection and danger. There are five gasdermins in humans - gasdermins A to E. Pyroptosis was first described in myeloid cells and mucosal epithelia, which express gasdermin D and activate it when cytosolic sensors of invasive infection or tissue damage assemble into large macromolecular structures, called inflammasomes. Inflammasomes recruit and activate inflammatory caspases (caspase 1, 4, 5, and 11), which cut gasdermin D to remove an inhibitory C-terminal domain, allowing the N-terminal domain to bind to membrane acidic lipids and oligomerize into pores. Recent studies have identified inflammasome-independent proteolytic pathways that activate gasdermin D and the other gasdermins. Here, we review inflammasome-independent pyroptosis pathways and what is known about their role in normal physiology and disease.

DOI: https://doi.org/10.1016/j.coi.2024.102432
Diabetes Metab J. 2024 Jun 10.

Diabetic Ketoacidosis as an Effect of Sodium-Glucose Cotransporter 2 Inhibitor: Real World Insights.

Han-Sang Baek, Chaiho Jeong, Yeoree Yang, Joonyub Lee, Jeongmin Lee, Seung-Hwan Lee, Jae Hyoung Cho, Tae-Seo Sohn, Hyun-Shik Son, Kun-Ho Yoon, Eun Young Lee.

  One of the notable adverse effects of sodium-glucose cotransporter 2 (SGLT2) inhibitor is diabetic ketoacidosis (DKA) often characterized by euglycemia. In this retrospective review of patients with DKA from 2015 to 2023, 21 cases of SGLT2 inhibitorassociated DKA were identified. Twelve (57.1%) exhibited euglycemic DKA (euDKA) while nine (42.9%) had hyperglycemic DKA (hyDKA). More than 90% of these cases were patients with type 2 diabetes mellitus. Despite similar age, sex, body mass index, and diabetes duration, individuals with hyDKA showed poorer glycemic control and lower C-peptide levels compared with euDKA. Renal impairment and acidosis were worse in the hyDKA group, requiring hemodialysis in two patients. Approximately one-half of hyDKA patients had concurrent hyperosmolar hyperglycemic state. Common symptoms included nausea, vomiting, general weakness, and dyspnea. Seizure was the initial manifestation of DKA in two cases. Infection and volume depletion were major contributors, while carbohydrate restriction and inadequate insulin treatment also contributed to SGLT2 inhibitor-associated DKA. Despite their beneficial effects, clinicians should be vigilant for SGLT2 inhibitor risk associated with DKA.

Keywords:  Diabetes mellitus; Diabetic ketoacidosis; Sodium-glucose transporter 2 inhibitors

DOI:  https://doi.org/10.4093/dmj.2024.0036
Life Sci. 2024 Jun 08. pii: S0024-3205(24)00404-1. [Epub ahead of print] 122814

Regulation of metabolism by circadian rhythms: Support from time-restricted eating, intestinal microbiota & omics analysis.

Ximei Xie, Mengjie Zhang, Hailing Luo.

  Circadian oscillatory system plays a key role in coordinating the metabolism of most organisms. Perturbation of genetic effects and misalignment of circadian rhythms result in circadian dysfunction and signs of metabolic disorders. The eating-fasting cycle can act on the peripheral circadian clocks, bypassing the photoperiod. Therefore, time-restricted eating (TRE) can improve metabolic health by adjusting eating rhythms, a process achieved through reprogramming of circadian genomes and metabolic programs at different tissue levels or remodeling of the intestinal microbiota, with omics technology allowing visualization of the regulatory processes. Here, we review recent advances in circadian regulation of metabolism, focus on the potential application of TRE for rescuing circadian dysfunction and metabolic disorders with the contribution of intestinal microbiota in between, and summarize the significance of omics technology.

Keywords:  Circadian rhythms; Intestinal microbiota; Metabolism; Omics; Time-restricted eating

DOI:  https://doi.org/10.1016/j.lfs.2024.122814