bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2022‒07‒31
five papers selected by
Matías Javier Monsalves Álvarez
Universidad de O’Higgins

  1. Biochim Biophys Acta Mol Basis Dis. 2022 Jul 25. pii: S0925-4439(22)00178-8. [Epub ahead of print] 166507
      AIMS: Sepsis is a life-threatening condition of organ dysfunction caused by dysregulated inflammation which predisposes patients to developing cardiovascular diseases. The ketone β-hydroxybutyrate is reported to be cardioprotective in cardiovascular diseases and this may be due to their signaling properties that contribute to reducing inflammation. While exogenous ketone esters (KE) increase blood ketone levels, it remains unknown whether KEs can reduce an enhanced inflammatory response and multi-organ dysfunction that is observed in sepsis. Thus, this study assesses whether a recently developed and clinically safe KE can effectively improve the inflammatory response and organ dysfunction in sepsis.METHODS AND RESULTS: To assess the anti-inflammatory effects of a KE, we utilized a model of lipopolysaccharide (LPS)-induced sepsis in which an enhanced inflammatory response results in multi-organ dysfunction. Oral administration of KE for three days prior to LPS-injection significantly protected mice against the profound systemic inflammation compared to their vehicle-treated counterparts. In assessing organ dysfunction, KE protected mice from sepsis-induced cardiac dysfunction as well as renal dysfunction and fibrosis. Furthermore, KE administration attenuated the sepsis-induced inflammation in the heart, kidney, and liver. Moreover, these protective effects occurred independent of changes to enzymes involved in ketone metabolism.
    CONCLUSION: These data show that using an exogenous KE attenuates the dysregulated systemic and organ inflammation as well as organ dysfunction in a model of severe inflammation. We postulate that this exogenous KE is an appealing and promising approach to capitalize on the protective anti-inflammatory effects of ketones in sepsis and/or other inflammatory responses.
    Keywords:  Inflammation; Ketone ester; NLRP3 inflammasome; β-Hydroxybutyrate
  2. J Pathol. 2022 Jul 27.
      Vascular calcification is an actively regulated process resembling bone formation and contributes to the cardiovascular morbidity and mortality of chronic kidney disease (CKD). However, effective therapy for vascular calcification is still lacking. The ketone body β-hydroxybutyrate (BHB) has been demonstrated to have health-promoting effects including anti-inflammation and cardiovascular protective effects. However, whether BHB protects against vascular calcification in CKD remains unclear. In this study, Alizarin Red staining and calcium content assay showed that BHB reduced calcification of vascular smooth muscle cells (VSMCs) and arterial rings. Of note, compared with CKD patients without thoracic calcification, serum BHB levels were lower in CKD patients with thoracic calcification. Supplementation with 1,3-butanediol (1,3-B), the precursor of BHB, attenuated aortic calcification in CKD rats and VitD3-overloaded mice. Furthermore, RNA-Seq analysis revealed that BHB downregulated HDAC9, which was further confirmed by RT-qPCR and western blot analysis. Both pharmacological inhibition and knockdown of HDAC9 attenuated calcification of human VSMCs, while overexpression of HDAC9 exacerbated calcification of VSMCs and aortic rings, indicating that HDAC9 promotes vascular calcification under CKD conditions. Of note, BHB treatment antagonized HDAC9-induced vascular calcification. In addition, HDAC9 overexpression activated NF-κB signaling pathway and inhibition of NF-κB attenuated HDAC9-induced VSMC calcification, suggesting that HDAC9 promotes vascular calcification via activation of NF-κB. In conclusion, our study demonstrates that BHB supplementation inhibits vascular calcification in CKD via modulation of the HDAC9-dependent NF-κB signaling pathway. Moreover, we unveil a crucial mechanistic role of HDAC9 in vascular calcification under CKD conditions, thus nutritional intervention or pharmacological approaches to enhance BHB levels could act as promising therapeutic strategies to target HDAC9 for the treatment of vascular calcification in CKD. This article is protected by copyright. All rights reserved.
    Keywords:  HDAC9; chronic kidney disease; vascular calcification; vascular smooth muscle cell; β-hydroxybutyrate
  3. Clin Sci (Lond). 2022 Jul 29. 136(14): 1081-1110
      Metabolic demands of skeletal muscle are substantial and are characterized normally as highly flexible and with a large dynamic range. Skeletal muscle composition (e.g., fiber type and mitochondrial content) and metabolism (e.g., capacity to switch between fatty acid and glucose substrates) are altered in obesity, with some changes proceeding and some following the development of the disease. Nonetheless, there are marked interindividual differences in skeletal muscle composition and metabolism in obesity, some of which have been associated with obesity risk and weight loss capacity. In this review, we discuss related molecular mechanisms and how current and novel treatment strategies may enhance weight loss capacity, particularly in diet-resistant obesity.
    Keywords:  metabolic disorders; metabolic regulation; mitochondria; oxidative phosphorylation; skeletal muscle
  4. Signal Transduct Target Ther. 2022 07 23. 7(1): 252
      Nutriments have been deemed to impact all physiopathologic processes. Recent evidences in molecular medicine and clinical trials have demonstrated that adequate nutrition treatments are the golden criterion for extending healthspan and delaying ageing in various species such as yeast, drosophila, rodent, primate and human. It emerges to develop the precision-nutrition therapeutics to slow age-related biological processes and treat diverse diseases. However, the nutritive advantages frequently diversify among individuals as well as organs and tissues, which brings challenges in this field. In this review, we summarize the different forms of dietary interventions extensively prescribed for healthspan improvement and disease treatment in pre-clinical or clinical. We discuss the nutrient-mediated mechanisms including metabolic regulators, nutritive metabolism pathways, epigenetic mechanisms and circadian clocks. Comparably, we describe diet-responsive effectors by which dietary interventions influence the endocrinic, immunological, microbial and neural states responsible for improving health and preventing multiple diseases in humans. Furthermore, we expatiate diverse patterns of dietotheroapies, including different fasting, calorie-restricted diet, ketogenic diet, high-fibre diet, plants-based diet, protein restriction diet or diet with specific reduction in amino acids or microelements, potentially affecting the health and morbid states. Altogether, we emphasize the profound nutritional therapy, and highlight the crosstalk among explored mechanisms and critical factors to develop individualized therapeutic approaches and predictors.
  5. Front Endocrinol (Lausanne). 2022 ;13 918923
      Treatment of obesity, an ongoing global epidemic, is challenging, as weight-loss efforts require a multidisciplinary approach addressing both behavioral and biologic needs that are not completely understood. Recent studies of the gut microbiome may provide better insight into the condition, and ultimately serve to advance more effective therapies. Research in this field has shifted from analyzing microbiome compositional differences to investigating functional changes that affect disease pathophysiology and outcome. Bacteria-derived metabolites are a way to bridge compositional changes to functional consequences. Through the production of metabolites, such as short chain fatty acids, tryptophan derivatives and bile acids, and interactions with peripheral and central signaling pathways, the gut microbiome may alter the body's metabolic and behavioral responses to food. Here, we summarize these mechanisms driven by gut-derived metabolites, through which the microbiome is thought to contribute to obesity, as well as review recent investigations of interventions related to these metabolites. Limitations of existing research, primarily due to paucity of causal studies in humans, are also discussed in this review.
    Keywords:  gut; microbiome; microbiota; obesity; weight