bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2022‒09‒11
eleven papers selected by
Matías Javier Monsalves Álvarez
  1. Current Evidence Concerning Effects of Ketogenic Diet and Intermittent Fasting in Patients with Nonalcoholic Fatty Liver.
  2. Ketogenic diet induced weight loss occurs independent of housing temperature and is followed by hyperphagia and weight regain after cessation in mice.
  3. Inhibition of monocarboxylate transporters (MCT) 1 and 4 reduces exercise capacity in mice.
  4. The Evolution of Ketosis: Potential Impact on Clinical Conditions.
  5. The Effect of Ketogenic Diet on Shared Risk Factors of Cardiovascular Disease and Cancer.
  6. Extra Virgin Olive Oil (EVOO), a Mediterranean Diet Component, in the Management of Muscle Mass and Function Preservation.
  7. THRIFTY, a novel high-throughput method for rapid fibre type identification of isolated skeletal muscle fibres.
  8. Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases.
  9. Myosin as a novel key modulator of striated muscle metabolism.
  10. Oxidative stress and inflammation regulation of sirtuins: New insights into common oral diseases.
  11. Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model.
  1. J Clin Transl Hepatol. 2022 Aug 28. 10(4): 730-739
    Current Evidence Concerning Effects of Ketogenic Diet and Intermittent Fasting in Patients with Nonalcoholic Fatty Liver.
    Pimsiri Sripongpun, Chaitong Churuangsuk, Chalermrat Bunchorntavakul.
      Nonalcoholic fatty liver disease (NAFLD) is emerging globally, while no therapeutic medication has been approved as an effective treatment to date, lifestyle intervention through dietary modification and physical exercise plays a critical role in NAFLD management. In terms of dietary modification, Mediterranean diet is the most studied dietary pattern and is recommended in many guidelines, however, it may not be feasible and affordable for many patients. Recently, a ketogenic diet and intermittent fasting have gained public attention and have been studied in the role of weight management. This article reviews specifically whether these trendy dietary patterns have an effect on NAFLD outcomes regarding intrahepatic fat content, fibrosis, and liver enzymes, the scientific rationales behind these particular dietary patterns, as well as the safety concerns in some certain patient groups.
    Keywords:  Ketogenic diet, Intermittent fasting; Lifestyle modification; Nonalcoholic fatty liver disease; Weight reduction
    DOI:  https://doi.org/10.14218/JCTH.2021.00494
  2. J Physiol. 2022 Sep 09.
    Ketogenic diet induced weight loss occurs independent of housing temperature and is followed by hyperphagia and weight regain after cessation in mice.
    Alyssa Weber, Kyle D Medak, Logan K Townsend, David C Wright.
      KEY POINTS: Ketogenic diets reduce food intake, increase energy expenditure and cause weight loss in rodents Prior preclinical studies have been completed at room temperature, a condition which induces thermal stress and limits clinical translatability We demonstrate that ketogenic diet-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are similar in mice housed at room temperature or thermal neutrality Ketogenic diet induced reductions in food intake appear to explain a large degree of weight loss. Similarly, switching mice from a ketogenic to an obesogenic diet leads to hyperphagia mediated weight gain ABSTRACT: Ketogenic diets (KDs) are a popular tool used for weight management. Studies in mice have demonstrated that KDs reduce food intake, increase energy expenditure and cause weight loss. These studies were completed at room temperature (RT), a condition below the animal's thermal neutral (TN) zone which induces thermal stress. As energy intake and expenditure are sensitive to environmental temperature it's not clear if a KD would exert the same beneficial effects under TN conditions. Adherence to restrictive diets is poor and consequently it is important to examine the effects, and underlying mechanisms, of cycling from a ketogenic to an obesogenic diet. The purpose of the current study was to determine if housing temperature impacted the effects of a KD in obese mice and to determine if the mechanisms driving KD-induced weight loss reverse when mice are switched to an obesogenic high fat diet. We demonstrate that KD-induced reductions in food intake, increases in energy expenditure, weight loss and improvements in glucose homeostasis are not dependent upon housing temperature. KD-induced weight loss, seems to be largely explained by reductions in caloric intake while cycling mice back to an obesogenic diet following a period of KD feeding leads to hyperphagia-induced weight gain. Collectively, our results suggest that prior findings with mice fed a KD at RT are likely not an artifact of how mice were housed and that initial changes in weight when transitioning from an obesogenic to a ketogenic diet or back, are largely dependent on food intake. Abstract figure legend The impact of housing temperature on ketogenic diet mediated changes in energy expenditure, food intake and weight gain. This article is protected by copyright. All rights reserved.
    Keywords:  energy expenditure; food intake; glucose tolerance; ketogenic diet; ketone; mice; obesity; weight gain
    DOI:  https://doi.org/10.1113/JP283469
  3. Physiol Rep. 2022 Sep;10(17): e15457
    Inhibition of monocarboxylate transporters (MCT) 1 and 4 reduces exercise capacity in mice.
    Yu Kitaoka, Kenya Takahashi, Hideo Hatta.
      The concept of lactate shuttle is widely accepted in exercise physiology. Lactate transport is mediated by monocarboxylate transporters (MCT), which enable cells to take up and release lactate. However, the role of lactate during exercise has not yet been fully elucidated. In this study, we investigated the effects of lactate transport inhibition on exercise capacity and metabolism in mice. Here, we demonstrated that MCT1 inhibition by α-cyano-4-hydroxycinnamate administration (4-CIN, 200 mg/g of body weight) reduced the treadmill running duration at 20 m/min. The administration of 4-CIN increased the blood lactate concentration immediately after exercise. With matched exercise duration, the muscle lactate concentration was higher while muscle glycogen content was lower in 4-CIN-administered mice. Further, we showed that MCT4 inhibition by bindarit administration (50 mg/kg of body weight) reduced the treadmill running duration at 40 m/min. Bindarit administration increased the muscle lactate but did not alter the blood lactate and glucose concentrations, as well as muscle glycogen content, immediately after exercise. A negative correlation was observed between exercise duration at 40 m/min and muscle lactate concentration immediately after exercise. Our results suggest that lactate transport via MCT1 and MCT4 plays a pivotal role in sustaining exercise.
    Keywords:  MCT; exercise; lactate; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.15457
  4. Nutrients. 2022 Sep 01. pii: 3613. [Epub ahead of print]14(17):
    The Evolution of Ketosis: Potential Impact on Clinical Conditions.
    Latha Nagamani Dilliraj, Giovanna Schiuma, Djidjell Lara, Giovanni Strazzabosco, James Clement, PierPaolo Giovannini, Claudio Trapella, Marco Narducci, Roberta Rizzo.
      Ketone bodies are small compounds derived from fatty acids that behave as an alternative mitochondrial energy source when insulin levels are low, such as during fasting or strenuous exercise. In addition to the metabolic function of ketone bodies, they also have several signaling functions separate from energy production. In this perspective, we review the main current data referring to ketone bodies in correlation with nutrition and metabolic pathways as well as to the signaling functions and the potential impact on clinical conditions. Data were selected following eligibility criteria accordingly to the reviewed topic. We used a set of electronic databases (Medline/PubMed, Scopus, Web of Sciences (WOS), Cochrane Library) for a systematic search until July 2022 using MeSH keywords/terms (i.e., ketone bodies, BHB, acetoacetate, inflammation, antioxidant, etc.). The literature data reported in this review need confirmation with consistent clinical trials that might validate the results obtained in in vitro and in vivo in animal models. However, the data on exogenous ketone consumption and the effect on the ketone bodies' brain uptake and metabolism might spur the research to define the acute and chronic effects of ketone bodies in humans and pursue the possible implication in the prevention and treatment of human diseases. Therefore, additional studies are required to examine the potential systemic and metabolic consequences of ketone bodies.
    Keywords:  anti-inflammatory; beta-hydroxybutyrate; evolution; ketogenesis
    DOI:  https://doi.org/10.3390/nu14173613
  5. Nutrients. 2022 Aug 25. pii: 3499. [Epub ahead of print]14(17):
    The Effect of Ketogenic Diet on Shared Risk Factors of Cardiovascular Disease and Cancer.
    Noushin Mohammadifard, Fahimeh Haghighatdoost, Mehran Rahimlou, Ana Paula Santos Rodrigues, Mohammadamin Khajavi Gaskarei, Paria Okhovat, Cesar de Oliveira, Erika Aparecida Silveira, Nizal Sarrafzadegan.
      Cardiovascular disease (CVD) and cancer are the first and second leading causes of death worldwide, respectively. Epidemiological evidence has demonstrated that the incidence of cancer is elevated in patients with CVD and vice versa. However, these conditions are usually regarded as separate events despite the presence of shared risk factors between both conditions, such as metabolic abnormalities and lifestyle. Cohort studies suggested that controlling for CVD risk factors may have an impact on cancer incidence. Therefore, it could be concluded that interventions that improve CVD and cancer shared risk factors may potentially be effective in preventing and treating both diseases. The ketogenic diet (KD), a low-carbohydrate and high-fat diet, has been widely prescribed in weight loss programs for metabolic abnormalities. Furthermore, recent research has investigated the effects of KD on the treatment of numerous diseases, including CVD and cancer, due to its role in promoting ketolysis, ketogenesis, and modifying many other metabolic pathways with potential favorable health effects. However, there is still great debate regarding prescribing KD in patients either with CVD or cancer. Considering the number of studies on this topic, there is a clear need to summarize potential mechanisms through which KD can improve cardiovascular health and control cell proliferation. In this review, we explained the history of KD, its types, and physiological effects and discussed how it could play a role in CVD and cancer treatment and prevention.
    Keywords:  cancer; cardiovascular disease; diabetes; hypertension; inflammation; ketogenic diet; obesity; oxidation
    DOI:  https://doi.org/10.3390/nu14173499
  6. Nutrients. 2022 Aug 30. pii: 3567. [Epub ahead of print]14(17):
    Extra Virgin Olive Oil (EVOO), a Mediterranean Diet Component, in the Management of Muscle Mass and Function Preservation.
    Sara Salucci, Anna Bartoletti-Stella, Alberto Bavelloni, Beatrice Aramini, William L Blalock, Francesco Fabbri, Ivan Vannini, Vittorio Sambri, Franco Stella, Irene Faenza.
      Aging results in a progressive decline in skeletal muscle mass, strength and function, a condition known as sarcopenia. This pathological condition is due to multifactorial processes including physical inactivity, inflammation, oxidative stress, hormonal changes, and nutritional intake. Physical therapy remains the standard approach to treat sarcopenia, although some interventions based on dietary supplementation are in clinical development. In this context, thanks to its known anti-inflammatory and antioxidative properties, there is great interest in using extra virgin olive oil (EVOO) supplementation to promote muscle mass and health in sarcopenic patients. To date, the molecular mechanisms responsible for the pathological changes associated with sarcopenia remain undefined; however, a complete understanding of the signaling pathways that regulate skeletal muscle protein synthesis and their behavior during sarcopenia appears vital for defining how EVOO might attenuate muscle wasting during aging. This review highlights the main molecular players that control skeletal muscle mass, with particular regard to sarcopenia, and discusses, based on the more recent findings, the potential of EVOO in delaying/preventing loss of muscle mass and function, with the aim of stimulating further research to assess dietary supplementation with EVOO as an approach to prevent or delay sarcopenia in aging individuals.
    Keywords:  aging; anabolic muscle pathways; muscle mass loss; olive oil phenols; sarcopenia
    DOI:  https://doi.org/10.3390/nu14173567
  7. J Physiol. 2022 Sep 07.
    THRIFTY, a novel high-throughput method for rapid fibre type identification of isolated skeletal muscle fibres.
    Oscar Horwath, Sebastian Edman, Alva Andersson, Filip J Larsen, William Apró.
      KEY POINTS: Skeletal muscle is composed of different fibre types, each with distinct physiological properties. To fully understand how skeletal muscle adapts to external cues such as exercise, nutrition and ageing, fibre type specific investigations are required. Such investigations are however very difficult to conduct due to the extreme time requirements related to classifying individually isolated muscle fibres. To bypass this issue, we have developed a rapid and reliable method named THRIFTY which is cheap as well as versatile and which can easily be implemented in most laboratories. THRIFTY increases the feasibility to conduct larger fibre-type specific studies and enables time-sensitive assays where measurements need to be carried out in close connection with tissue sampling By using THRIFTY, new insights into fibre type-specific muscle physiology can be gained which may have broad implications in health and disease ABSTRACT: Fibre type-specific analyses are required for broader understanding of muscle physiology, but such analyses are difficult to conduct due to the extreme time requirements of dissecting and fibre typing individual fibres. Investigations are often confined to a small number of fibres from few participants with low representativeness of the entire fibre population and the participant population. To increase the feasibility of conducting large-scale fibre type-specific studies, a valid and rapid method for high-throughput fibre typing of individually dissected fibres was developed. Employing THRIFTY (High-Throughput Immunofluorescence Fibre Typing), 400 fibre segments were fixed onto microscope slides with a pre-printed coordinated grid system, probed with antibodies against MyHC-I and MyHC-II and classified using a fluorescence microscope. The validity and speed of THRIFTY was compared to a previously validated protocol (dot blot) on a fibre-to-fibre basis. Fibre pool purity was evaluated using 'gold standard' SDS-PAGE and silver staining. A modified THRIFTY-protocol using fluorescent western blot equipment was also validated. THRIFTY displayed excellent agreement with the dot blot protocol, κ = 0,955 (95% CI, 0,928 to 0,982), P < 0.001. Both the original and modified THRIFTY protocols generated type I and type II fibre pools of absolute purity. Using THRIFTY, 400 fibres were typed just under 11 hours, which was approximately 3 times faster than dot blot. THRIFTY is a novel and valid method with high versatility for very rapid fibre typing of individual fibres. THRIFTY can therefore facilitate the generation of large fibre pools for more extensive mechanistic studies into skeletal muscle physiology. Absract figure legend Large scale investigations into fibre type-specific physiology are limited by the extreme time requirements related to classifying individually isolated muscle fibres. To increase the feasibility of such studies, we developed a rapid and reliable fibre-typing method which we have named THRIFTY. Additional benefits of THRIFTY, beyond high speed and validity, include high versatility, excellent scalability, and low cost. The many benefits of THRIFTY increase the feasibility to generate large pools of pure type I and type II muscle fibres which can be used for multiple downstream analyses. The high speed of THRIFTY also enables time-sensitive assays where measurements need to be carried out in close connection with tissue sampling. Employing THRIFTY may therefore provide new insights into fibre type-specific muscle physiology which may have broad implications in health and disease. This article is protected by copyright. All rights reserved.
    Keywords:  MyHC; SDS-PAGE; fibre typing; high-throughput; immunofluorescence
    DOI:  https://doi.org/10.1113/JP282959
  8. Rev Neurosci. 2022 Sep 06.
    Mitochondrial fission mediated by Drp1-Fis1 pathway and neurodegenerative diseases.
    Wenjia Shi, Cheng Tan, Can Liu, Dan Chen.
      In recent years, the role of mitochondrial dynamics in neurodegenerative diseases has becoming increasingly important. More and more evidences have shown that in pathological conditions, abnormal mitochondrial divisions, especially Drp1-Fis1-mediated divisions, play an important role in the occurrence and development of Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, glaucoma, and other neurodegenerative diseases. This review highlights several new mechanisms of physiological fission of mitochondria and the difference/connection of physiological/pathological mitochondrial fission. In addition, we described the relationship between abnormal mitochondrial dynamics and neurodegenerative diseases in detail and emphatically summarized its detection indicators in basic experiments, trying to provide references for further mechanism exploration and therapeutic targets.
    Keywords:  Drp1; Fis1; mitochondrial dynamics; neurodegenerative diseases; pathological fission; physiological fission
    DOI:  https://doi.org/10.1515/revneuro-2022-0056
  9. Physiology (Bethesda). 2022 Sep 06.
    Myosin as a novel key modulator of striated muscle metabolism.
    Christopher T A Lewis, Julien Ochala.
      After years of intense research using structural, biological, and biochemical experimental procedures, it is clear that myosin molecules are essential for striated muscle contraction. However, this is just the tip of the iceberg of their function. Interestingly, recently, it has been shown that these molecules (especially myosin heavy chains) are also crucial for cardiac and skeletal muscle relaxed state. In the present review, we first overview myosin heavy chain biochemical states and how they influence the consumption of ATP. We then detail how neighbouring partner proteins including myosin light chains and myosin binding protein C intervene in such processes, modulating energy demand in health and disease. Finally, we present current experimental drugs targeting myosin ATP consumption and how they can treat muscle diseases.
    Keywords:  Heart; Metabolism; Myosin; Skeletal muscle
    DOI:  https://doi.org/10.1152/physiol.00018.2022
  10. Front Physiol. 2022 ;13 953078
    Oxidative stress and inflammation regulation of sirtuins: New insights into common oral diseases.
    Zijian Pan, Hao Dong, Ning Huang, Jie Fang.
      Sirtuins are a family of nicotinamide adenine dinucleotide (NAD)+-dependent histone deacetylases, comprising seven members SIRT1-SIRT7. Sirtuins have been extensively studied in regulating ageing and age-related diseases. Sirtuins are also pivotal modulators in oxidative stress and inflammation, as they can regulate the expression and activation of downstream transcriptional factors (such as Forkhead box protein O3 (FOXO3a), nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-kappa B (NF-κB)) as well as antioxidant enzymes, through epigenetic modification and post-translational modification. Most importantly, studies have shown that aberrant sirtuins are involved in the pathogenesis of infectious and inflammatory oral diseases, and oral cancer. In this review, we provide a comprehensive overview of the regulatory patterns of sirtuins at multiple levels, and the essential roles of sirtuins in regulating inflammation, oxidative stress, and bone metabolism. We summarize the involvement of sirtuins in several oral diseases such as periodontitis, apical periodontitis, pulpitis, oral candidiasis, oral herpesvirus infections, dental fluorosis, and oral cancer. At last, we discuss the potential utilization of sirtuins as therapeutic targets in oral diseases.
    Keywords:  bone regulation; inflammation; oral diseases; sirtuins; stress
    DOI:  https://doi.org/10.3389/fphys.2022.953078
  11. Int J Mol Sci. 2022 Sep 01. pii: 9954. [Epub ahead of print]23(17):
    Caffeine Inhibits NLRP3 Inflammasome Activation by Downregulating TLR4/MAPK/NF-κB Signaling Pathway in an Experimental NASH Model.
    Eduardo E Vargas-Pozada, Erika Ramos-Tovar, Juan D Rodriguez-Callejas, Irina Cardoso-Lezama, Silvia Galindo-Gómez, Daniel Talamás-Lara, Verónica Rocío Vásquez-Garzón, Jaime Arellanes-Robledo, Víctor Tsutsumi, Saúl Villa-Treviño, Pablo Muriel.
      Caffeine elicits protective effects against liver diseases, such as NASH; however, its mechanism of action involving the pyrin domain-containing-3 (NLRP3) inflammasome signaling pathway remains to be elucidated. This study aimed to evaluate the effect of caffeine on the NLRP3 inflammasome signaling pathway in a rat model of NASH. NASH was induced by feeding rats a high-fat, -sucrose, and -cholesterol diet (HFSCD) for 15 weeks along with a weekly low dose (400 mg/kg, i.p.) of CCl4. Caffeine was administered at 50 mg/kg p.o. The effects of HFSCD+CCl4 and caffeine on the liver were evaluated using biochemical, ultrastructural, histological, and molecular biological approaches. The HFSCD+CCl4-treated rats showed fat accumulation in the liver, elevated levels of inflammatory mediators, NLRP3 inflammasome activation, antioxidant dysregulation, and liver fibrosis. Caffeine reduced necrosis, cholestasis, oxidative stress, and fibrosis. Caffeine exhibited anti-inflammatory effects by attenuating NLRP3 inflammasome activation. Moreover, caffeine prevented increases in toll-like receptor 4 (TLR4) and nuclear factor-κB (NF-κB) protein levels and mitigated the phosphorylation of mitogen-activated protein kinase (MAPK). Importantly, caffeine prevented the activation of hepatic stellate cells. This study is the first to report that caffeine ameliorates NASH by inhibiting NLRP3 inflammasome activation through the suppression of the TLR4/MAPK/NF-κB signaling pathway.
    Keywords:  caffeine; leucine-rich-containing family; mitogen-activated protein kinase; non-alcoholic steatohepatitis; nuclear factor-κB; nucleotide-binding domain; pyrin domain-containing-3 inflammasome; toll-like receptor 4
    DOI:  https://doi.org/10.3390/ijms23179954
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