bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2022–09–04
ten papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.
  2. Branched-chain amino acids and mitochondrial biogenesis: an overview and mechanistic summary.
  3. A Review of Ketogenic Diet and Lifestyle.
  4. The emerging role of skeletal muscle as a modulator of lipid profile the role of exercise and nutrition.
  5. Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease.
  6. The skeletal muscle circadian clock regulates titin splicing through RBM20.
  7. Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?
  8. Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
  9. Ketogenic diet: an effective treatment approach for neurodegenerative diseases.
  10. Short-chain fatty acids are key mediators of the favorable effects of the Mediterranean diet on intestinal barrier integrity: data from the randomized controlled LIBRE trial.
  1. Open Life Sci. 2022 ;17(1): 856-864
    β-Hydroxybutyrate upregulates FGF21 expression through inhibition of histone deacetylases in hepatocytes.
    Aili Yan, Yanyan Zhao, Lijun Zhang, Xiangyan Liang, Xiaochun Zhang, Fenli Liang, Shen Nian, Xinhua Li, Zhuo Sun, Ke Li, Yu-Feng Zhao.
      Fibroblast growth factor 21 (FGF21) is secreted by hepatocytes as a peptide hormone to regulate glucose and lipid metabolism. FGF21 promotes hepatic ketogenesis and increases ketone body utilization in starvation. Histones are the target molecules of nutrients in regulating hepatic metabolic homeostasis. However, the effect of ketone bodies on FGF21 expression and the involvement of histones in it is not clear yet. The present study observed the effects of β-hydroxybutyrate (β-OHB), the main physiological ketone body, on FGF21 expression in human hepatoma HepG2 cells in vitro and in mice in vivo, and the role of histone deacetylases (HDACs) in β-OHB-regulated FGF21 expression was investigated. The results showed that β-OHB significantly upregulated FGF21 gene expression and increased FGF21 protein levels while it inhibited HDACs' activity in HepG2 cells. HDACs' inhibition by entinostat upregulated FGF21 expression and eliminated β-OHB-stimulated FGF21 expression in HepG2 cells. Intraperitoneal injections of β-OHB in mice resulted in the elevation of serum β-OHB and the inhibition of hepatic HDACs' activity. Meanwhile, hepatic FGF21 expression and serum FGF21 levels were significantly increased in β-OHB-treated mice compared with the control. It is suggested that β-OHB upregulates FGF21 expression through inhibition of HDACs' activity in hepatocytes.
    Keywords:  fibroblast growth factor 21; hepatocyte; histone deacetylases; β-hydroxybutyrate
    DOI:  https://doi.org/10.1515/biol-2022-0095
  2. Mol Nutr Food Res. 2022 Sep 01. e2200109
    Branched-chain amino acids and mitochondrial biogenesis: an overview and mechanistic summary.
    Jason S Hinkle, Caroline N Rivera, Roger A Vaughan.
      Branched-chain amino acids (BCAA) are essential in the diet and promote several vital cell responses which may have benefits for health and athletic performance, as well as disease prevention. While BCAA are well-known for their ability to stimulate muscle protein synthesis, their effects on cell energetics are also becoming well-documented, but these receive less attention. In this review, we highlight much of the current evidence demonstrating BCAA ability (as individual amino acids or as part of dietary mixtures) to alter regulators of cellular energetics with an emphasis on mitochondrial biogenesis and related signaling. Several studies have shown, both in vitro and in vivo, that BCAA (either individual or as a mixture) may promote signaling associated with increased mitochondrial biogenesis including the upregulation of master regulator of mitochondrial biogenesis peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), as well as numerous downstream targets and related function. However, sparse data in humans and the difficulty of controlling variables associated with feeding studies leaves the physiological relevance of these findings unclear. Future well-controlled diet studies will be needed to assess if BCAA consumption is associated with increased mitochondrial biogenesis and improved metabolic outcomes in healthy and/or diseased human populations. This article is protected by copyright. All rights reserved.
    Keywords:  isoleucine; leucine; mitochondrial biogenesis; skeletal muscle; valine
    DOI:  https://doi.org/10.1002/mnfr.202200109
  3. Mo Med. 2022 Jan-Feb;119(1):119(1): 84-88
    A Review of Ketogenic Diet and Lifestyle.
    Erin McGaugh, Brandon Barthel.
      The ketogenic diet has become increasing popular in recent years. With 25.4 million unique searches, the keto diet was the most Googled diet in the United States in 2020.1 With increased consumer interest, the "keto" food industry has grown rapidly, and as a result, the global ketogenic diet market was valued at $9.57 billion in 2019.2 The ketogenic diet has been discussed in popular culture by celebrities, health magazines, and documentaries. The popularity of this diet, and diets in general may be explained by the obesity epidemic in the United States and Missouri.
  4. Lipids Health Dis. 2022 Aug 30. 21(1): 81
    The emerging role of skeletal muscle as a modulator of lipid profile the role of exercise and nutrition.
    Tzortzis Nomikos, Spyridon Methenitis, Demosthenes B Panagiotakos.
      The present article aims to discuss the hypothesis that skeletal muscle per se but mostly its muscle fiber composition could be significant determinants of lipid metabolism and that certain exercise modalities may improve metabolic dyslipidemia by favorably affecting skeletal muscle mass, fiber composition and functionality. It discusses the mediating role of nutrition, highlights the lack of knowledge on mechanistic aspects of this relationship and proposes possible experimental directions in this field.
    Keywords:  Dyslipidemia; Exercise protocols; Intramuscular triglycerides; Lipid profile; Muscle fibers; Skeletal muscle
    DOI:  https://doi.org/10.1186/s12944-022-01692-0
  5. Front Physiol. 2022 ;13 866792
    Exercise as an Aging Mimetic: A New Perspective on the Mechanisms Behind Exercise as Preventive Medicine Against Age-Related Chronic Disease.
    Wesley K Lefferts, Mary M Davis, Rudy J Valentine.
      Age-related chronic diseases are among the most common causes of mortality and account for a majority of global disease burden. Preventative lifestyle behaviors, such as regular exercise, play a critical role in attenuating chronic disease burden. However, the exact mechanism behind exercise as a form of preventative medicine remains poorly defined. Interestingly, many of the physiological responses to exercise are comparable to aging. This paper explores an overarching hypothesis that exercise protects against aging/age-related chronic disease because the physiological stress of exercise mimics aging. Acute exercise transiently disrupts cardiovascular, musculoskeletal, and brain function and triggers a substantial inflammatory response in a manner that mimics aging/age-related chronic disease. Data indicate that select acute exercise responses may be similar in magnitude to changes seen with +10-50 years of aging. The initial insult of the age-mimicking effects of exercise induces beneficial adaptations that serve to attenuate disruption to successive "aging" stimuli (i.e., exercise). Ultimately, these exercise-induced adaptations reduce the subsequent physiological stress incurred from aging and protect against age-related chronic disease. To further examine this hypothesis, future work should more intricately describe the physiological signature of different types/intensities of acute exercise in order to better predict the subsequent adaptation and chronic disease prevention with exercise training in healthy and at-risk populations.
    Keywords:  aging; exercise physiology; physiological mechanisms; preventive medicine; stress adaptation
    DOI:  https://doi.org/10.3389/fphys.2022.866792
  6. Elife. 2022 Sep 01. pii: e76478. [Epub ahead of print]11
    The skeletal muscle circadian clock regulates titin splicing through RBM20.
    Lance A Riley, Xiping Zhang, Collin M Douglas, Joseph M Mijares, David W Hammers, Christopher A Wolff, Neil B Wood, Hailey R Olafson, Ping Du, Siegfried Labeit, Michael J Previs, Eric T Wang, Karyn A Esser.
      Circadian rhythms are maintained by a cell autonomous, transcriptional-translational feedback loop known as the molecular clock. While previous research suggests a role of the molecular clock in regulating skeletal muscle structure and function, no mechanisms have connected the molecular clock to sarcomere filaments. Utilizing inducible, skeletal muscle specific, Bmal1 knockout (iMSBmal1-/-) mice, we showed that knocking out skeletal muscle clock function alters titin isoform expression using RNAseq, LC-MS, and SDS-VAGE. This alteration in titin's spring length resulted in sarcomere length heterogeneity. We demonstrate the direct link between altered titin splicing and sarcomere length in vitro using U7 snRNPs that truncate the region of titin altered in iMSBmal1-/- muscle. We identified a mechanism whereby the skeletal muscle clock regulates titin isoform expression through transcriptional regulation of Rbm20, a potent splicing regulator of titin. Lastly, we used an environmental model of circadian rhythm disruption and identified significant down-regulation of Rbm20 expression. Our findings demonstrate the importance of the skeletal muscle circadian clock in maintaining titin isoform through regulation of RBM20 expression. Because circadian rhythm disruption is a feature of many chronic diseases, our results highlight a novel pathway that could be targeted to maintain skeletal muscle structure and function in a range of pathologies.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.76478
  7. APL Bioeng. 2022 Sep;6(3): 031502
    Mechanoimmunology: Are inflammatory epigenetic states of macrophages tuned by biophysical factors?
    Nikhil Jain, Janet M Lord, Viola Vogel.
      Many inflammatory diseases that are responsible for a majority of deaths are still uncurable, in part as the underpinning pathomechanisms and how to combat them is still poorly understood. Tissue-resident macrophages play pivotal roles in the maintenance of tissue homeostasis, but if they gradually convert to proinflammatory phenotypes, or if blood-born proinflammatory macrophages persist long-term after activation, they contribute to chronic inflammation and fibrosis. While biochemical factors and how they regulate the inflammatory transcriptional response of macrophages have been at the forefront of research to identify targets for therapeutic interventions, evidence is increasing that physical factors also tune the macrophage phenotype. Recently, several mechanisms have emerged as to how physical factors impact the mechanobiology of macrophages, from the nuclear translocation of transcription factors to epigenetic modifications, perhaps even DNA methylation. Insight into the mechanobiology of macrophages and associated epigenetic modifications will deliver novel therapeutic options going forward, particularly in the context of increased inflammation with advancing age and age-related diseases. We review here how biophysical factors can co-regulate pro-inflammatory gene expression and epigenetic modifications and identify knowledge gaps that require urgent attention if this therapeutic potential is to be realized.
    DOI:  https://doi.org/10.1063/5.0087699
  8. Cell Stem Cell. 2022 Sep 01. pii: S1934-5909(22)00346-0. [Epub ahead of print]29(9): 1287-1289
    Fission impossible: Mitochondrial dynamics direct muscle stem cell fates.
    Ji-Hyung Lee, Foteini Mourkioti.
      Muscle stem cells (MuSCs) exhibit different metabolic profiles depending on their activity, however the mechanisms by which mitochondria affect MuSC fate has been understudied. In this issue of Cell Stem Cell, Hong et al. (2022) and Baker et al. (2022) demonstrate that defects in mitochondrial dynamics hinder proper MuSC activation and impair muscle regeneration.
    DOI:  https://doi.org/10.1016/j.stem.2022.08.010
  9. Curr Neuropharmacol. 2022 Aug 30.
    Ketogenic diet: an effective treatment approach for neurodegenerative diseases.
    Ye Tao, Sean X Leng, Haiyan Zhang.
      This review discusses the effects and mechanisms of ketogenic diet on neurodegenerative diseases on the basis of available evidence. A ketogenic diet refers to a high-fat, medium-protein, and low-carbohydrate diet that leads to a metabolic shift to ketosis. This review systematically summarizes the scientific literature supporting this effective treatment approach for neurodegenerative diseases, including effects on mitochondrial function, oxidative stress, neuronal apoptosis, neuroinflammation, and the microbiota-gut-brain axis. It also highlights the clinical evidence for the effects of ketogenic diet in the treatment of Alzheimer's disease, Parkinson's disease, and motor neuron disease. Finally, it discusses the common adverse effects of ketogenic therapy. Although the complete mechanism of ketogenic diet in the treatment of neurodegenerative diseases remains to be elucidated, its clinical efficacy has attracted many new followers. The ketogenic diet is a good candidate for adjuvant therapy, but its specific applicability depends on the type and the degree of the disease.
    Keywords:  Alzheimer's disease ; Amyotrophic lateral sclerosis ; Ketogenic diet ; Parkinson's disease ; microbiota–gut–brain axis; neurodegenerative diseases
    DOI:  https://doi.org/10.2174/1570159X20666220830102628
  10. Am J Clin Nutr. 2022 Sep 02. pii: nqac175. [Epub ahead of print]
    Short-chain fatty acids are key mediators of the favorable effects of the Mediterranean diet on intestinal barrier integrity: data from the randomized controlled LIBRE trial.
    Benjamin Seethaler, Nguyen K Nguyen, Maryam Basrai, Marion Kiechle, Jens Walter, Nathalie M Delzenne, Stephan C Bischoff.
       BACKGROUND: The Mediterranean diet is associated with the prevention of diabetes, cardiovascular disease, and cancer, all of which are linked to intestinal barrier impairment.
    OBJECTIVES: Here, we hypothesize that the Mediterranean diet, possibly via the induction of short-chain fatty acids (SCFAs), improves intestinal barrier integrity. Furthermore, we aim to establish novel personalized nutrition advice based on machine learning algorithms.
    METHODS: We studied 260 women with intestinal barrier impairment. The women were allocated to follow either a Mediterranean diet or a control diet for 3 mo. Intestinal permeability was assessed by measuring lipopolysaccharide binding protein (LBP) in plasma and zonulin in feces. SCFA concentrations were analyzed in feces. Bi- and multivariate analyses and machine learning algorithms (random forest classification) were conducted.
    RESULTS: Particularly in the intervention group, adherence to the Mediterranean diet increased, whereas plasma LBP and fecal zonulin concentrations decreased (all q < 0.001 for the intervention group, all q < 0.1 for control group). In the intervention group, fecal SCFA concentrations increased (propionate + 19%; butyrate + 44%; both q < 0.001). Multivariate analyses showed that adherence to the Mediterranean diet was associated with SCFA concentrations (all q < 0.001) and inversely associated with LBP and zonulin concentrations (all q < 0.02). Mediation analyses identified propionate and butyrate as the key mechanistic link between diet and intestinal permeability integrity. Accordingly, using baseline SCFA data, we could predict the effect of the Mediterranean diet on intestinal permeability using a machine learning algorithm (receiver operating characteristic AUC: 0.78-0.96).
    CONCLUSIONS: Our data suggest that SCFAs are key mediators for the relation between diet and gut health. Assessment of SCFAs may form a basis for personalized nutrition in future clinical care. These results need to be verified in larger studies powered for this purpose, comprising different study populations. The trial was registered at clinicaltrials.gov as NCT02087592 and NCT02516540.
    Keywords:  Mediterranean diet; breast cancer; dietary fibers; gut barrier; machine learning; mediation analyses; personalized nutrition; precision nutrition; short-chain fatty acids
    DOI:  https://doi.org/10.1093/ajcn/nqac175
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