bims-kimdis Biomed News
on Ketones, inflammation and mitochondria in disease
Issue of 2023–12–03
twelve papers selected by
Matías Javier Monsalves Álvarez, Universidad de O’Higgins
  1. Ketogenic therapies in Parkinson's disease, Alzheimer's disease, and mild cognitive impairment: An integrative review.
  2. Reversible histone deacetylase activity catalyzes lysine acylation.
  3. What We Have Learned About Combining a Ketogenic Diet and Chemoimmunotherapy: a Case Report and Review of Literature.
  4. BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway.
  5. [Beneficial effects of ketogenic diet for Alzheimer's disease management].
  6. The effects of the ketogenic diet for the management of type 2 diabetes mellitus: A systematic review and meta-analysis of recent studies.
  7. Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.
  8. Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity.
  9. Ketone Production and Excretion Even During Mild Hyperglycemia and the Impact of Sodium-Glucose Co-transporter Inhibition in Type 1 Diabetes.
  10. Mitochondrial quality control in health and cardiovascular diseases.
  11. Physiological 4-phenylbutyrate promotes mitochondrial biogenesis and metabolism in C2C12 myotubes.
  12. Muscle glycogen depletion: a weak-link rendering muscle cells prone to potassium-induced fatigue?
  1. Appl Nurs Res. 2023 Dec;pii: S0897-1897(23)00079-4. [Epub ahead of print]74 151745
    Ketogenic therapies in Parkinson's disease, Alzheimer's disease, and mild cognitive impairment: An integrative review.
    Susan Price, Todd M Ruppar.
       BACKGROUND: Ketogenic therapies have shown benefit for seizure reduction in epilepsy but their impact on other neurologic conditions is less known. In this literature review, the efficacy of ketogenic therapies were assessed in Parkinson's disease (PD), Alzheimer's disease (AD), and mild cognitive impairment (MCI).
    METHODS: A literature search was conducted using PubMed, Scopus, and Google Scholar focusing on ketogenic therapies in PD, AD, and MCI.
    RESULTS: A total of 2565 records were identified with a total of 15 studies (3 for PD and 12 for MCI/AD) meeting criteria for analysis. The ketogenic diet was used in all the PD studies and did show significant improvement in motor function either through vocal quality, gait, freezing, tremor, and/or balance. A variety of ketogenic therapies were utilized in the MCI and AD groups including a ketogenic diet, low-carbohydrate diet, modified Adkins diet, Mediterranean diet with coconut oil supplementation, a ketogenic diet with a ketogenic medium chain triglyceride (kMCT) supplement, as well as ketogenic supplements including a ketogenic drink with kMCT, oral ketogenic compounds (Axona and AC-1202), and MCT oil or emulsion. The ketogenic diet independently showed a non-significant trend towards improvement in cognition. The Mediterranean diet, modified Adkins diet, and low-carbohydrate diet showed statistically significant improvements in some, although not all, of their cognitive measures. Use of ketogenic supplements, drinks, or compounds showed variable results in the AD and MCI groups. The Axona and AC-1202 compounds showed no significant improvement in cognition at the end of their respective 90-day trials. Most MCT supplements did show cognitive improvements, although only after 6 months of adherence. Adherence to the intervention was problematic in most of the diet studies.
    CONCLUSION: Ketogenic therapies have promise in PD, AD, and MCI for symptom improvement although larger studies are needed to support their implementation in clinical practice.
    Keywords:  Alzheimer's disease; Cognitive dysfunction; Ketogenic diet; Neurodegenerative disorder; Parkinson's disease
    DOI:  https://doi.org/10.1016/j.apnr.2023.151745
  2. bioRxiv. 2023 Nov 17. pii: 2023.11.17.567549. [Epub ahead of print]
    Reversible histone deacetylase activity catalyzes lysine acylation.
    Takeshi Tsusaka, Mohd Altaf Najar, Benjamin Schwarz, Eric Bohrnsen, Juan A Oses-Prieto, Christina Lee, Alma L Burlingame, Catharine M Bosio, George M Burslem, Emily L Goldberg.
      Starvation and low carbohydrate diets lead to the accumulation of the ketone body, β-hydroxybutyrate (BHB), whose blood concentrations increase more than 10-fold into the millimolar range. In addition to providing a carbon source, BHB accumulation triggers lysine β-hydroxybutyrylation (Kbhb) of proteins via unknown mechanisms. As with other lysine acylation events, Kbhb marks can be removed by histone deacetylases (HDACs). Here, we report that class I HDACs unexpectedly catalyze protein lysine modification with β-hydroxybutyrate (BHB). Mutational analyses of the HDAC2 active site reveal a shared reliance on key amino acids for classical deacetylation and non-canonical HDAC-catalyzed β-hydroxybutyrylation. Also consistent with reverse HDAC activity, Kbhb formation is driven by mass action and substrate availability. This reverse HDAC activity is not limited to BHB but also extends to multiple short-chain fatty acids. The reversible activity of class I HDACs described here represents a novel mechanism of PTM deposition relevant to metabolically-sensitive proteome modifications.
    DOI:  https://doi.org/10.1101/2023.11.17.567549
  3. Fed Pract. 2023 Aug;40(Suppl 3): S98-S104
    What We Have Learned About Combining a Ketogenic Diet and Chemoimmunotherapy: a Case Report and Review of Literature.
    Daniel Sims, Agnes K Liman, Victoria Leung, Andrew Hwang, Jeffrey Means, Andrew D Liman.
       Background: A high-fat, moderate-protein, low-carbohydrate ketogenic diet has been reported in the literature as a treatment option for patients with cancer.
    Case Presentation: A 69-year-old veteran was initially diagnosed with stage III colorectal cancer and progressed to having liver, pancreatic, and omental lymph node involvement despite completing adjuvant FOLFOX (fluorouracil, leucovorin calcium, and oxaliplatin) after surgery. The patient was treated with FOLFIRI (fluorouracil, leucovorin calcium, and irinotecan hydrochloride) and bevacizumab, followed by encorafenib and cetuximab on progression. Subsequently, he received pembrolizumab but continued to progress. The patient was later placed on trifluridine/tipiracil and bevacizumab concurrent with a ketogenic diet. Positron emission tomography and carcinoembryonic antigen levels indicated disease stabilization for 10 months. On progression, the patient was transitioned to ipilumimab and nivolumab and continued to adhere to the ketogenic diet. The patient's disease has continued to remain stable for the past 1 year. His degree of ketosis was determined using the glucose ketone index. The patient continues to have a good quality of life during concurrent ketogenic diet and therapy.
    Conclusions: This case supports the tolerability of the ketogenic diet along with chemotherapy and immunotherapy and should be considered as an adjunct to standard cancer treatment. In this report, we reviewed the latest literature about cellular mechanism of the ketogenic diet and the efficacy and relationship with chemotherapy and immunotherapy. We are about to open a ketogenic diet protocol at the Veterans Affairs Central California Health Care System in Fresno.
    DOI:  https://doi.org/10.12788/fp.0399
  4. Aging (Albany NY). 2023 Nov 27. 15
    BDH1-mediated βOHB metabolism ameliorates diabetic kidney disease by activation of NRF2-mediated antioxidative pathway.
    Sheng-Rong Wan, Fang-Yuan Teng, Wei Fan, Bu-Tuo Xu, Xin-Yue Li, Xiao-Zhen Tan, Man Guo, Chen-Lin Gao, Chun-Xiang Zhang, Zong-Zhe Jiang, Yong Xu.
      A ketogenic diet (KD) and β-hydroxybutyrate (βOHB) have been widely reported as effective therapies for metabolic diseases. β-Hydroxybutyrate dehydrogenase 1 (BDH1) is the rate-limiting enzyme in ketone metabolism. In this study, we examined the BDH1-mediated βOHB metabolic pathway in the pathogenesis of diabetic kidney disease (DKD). We found that BDH1 is downregulated in the kidneys in DKD mouse models, patients with diabetes, and high glucose- or palmitic acid-induced human renal tubular epithelial (HK-2) cells. BDH1 overexpression or βOHB treatment protects HK-2 cells from glucotoxicity and lipotoxicity by inhibiting reactive oxygen species overproduction. Mechanistically, BDH1-mediated βOHB metabolism activates NRF2 by enhancing the metabolic flux of βOHB-acetoacetate-succinate-fumarate. Moreover, in vivo studies showed that adeno-associated virus 9-mediated BDH1 renal expression successfully reverses fibrosis, inflammation, and apoptosis in the kidneys of C57 BKS db/db mice. Either βOHB supplementation or KD feeding could elevate the renal expression of BDH1 and reverse the progression of DKD. Our results revealed a BDH1-mediated molecular mechanism in the pathogenesis of DKD and identified BDH1 as a potential therapeutic target for DKD.
    Keywords:  BDH1; NRF2; diabetic kidney disease; metabolism; βOHB
    DOI:  https://doi.org/10.18632/aging.205248
  5. Biol Aujourdhui. 2023 ;217(3-4): 253-263
    [Beneficial effects of ketogenic diet for Alzheimer's disease management].
    Anouk Charlot, Alix Lernould, Irène Plus, Joffrey Zoll.
      Alzheimer's disease (AD) is a neurodegenerative disease that affects almost 1 million people in France and 55 million in the world. This pathology is a global health preoccupation because of the lack of efficient curative treatment and the increase of its prevalence. During the last decade, the comprehension of pathophysiological mechanisms involved in AD have been improved. Amyloid plaques and neurofibrillary tangles accumulation are characteristic of Alzheimer's brain patients, accompanied by increased brain inflammation and oxidative stress, impaired cerebral metabolism of glucose and mitochondrial function. Treatment of AD includes different approaches, as pharmacology, psychology support, physiotherapy, and speech therapy. However, these interventions do not have a curative effect, but only compensatory on the disease. Ketogenic diet (KD), a low-carbohydrates and high-fat diet, associated with a medium-chain triglycerides intake (MCTs) might induce benefices for Alzheimer disease patients. Carbohydrate restriction and MCTs promotes the production of ketone bodies from fatty acid degradation. These metabolites replacing glucose, serve the brain as energetic substrates, and induce neuroprotective effects. Such a nutritional support might slow down the disease progression and improve cognitive abilities of patients. This review aims to examine the neuroprotective mechanisms of KD in AD progression and describes the advantages and limitations of KD as a therapeutic strategy.
    Keywords:  Alzheimer’s disease; corps cétoniques; glucose; ketogenic diet; ketone bodies; maladie d’Alzheimer; medium chain triglycerides; régime cétogène; triglycérides à chaîne moyenne
    DOI:  https://doi.org/10.1051/jbio/2023031
  6. Diabetes Metab Syndr. 2023 Nov 15. pii: S1871-4021(23)00201-1. [Epub ahead of print]17(12): 102905
    The effects of the ketogenic diet for the management of type 2 diabetes mellitus: A systematic review and meta-analysis of recent studies.
    Kimberley Yu Ching Choy, Jimmy Chun Yu Louie.
       OBJECTIVE: To systematically review the effects of the ketogenic diet on glycaemic control, body weight, cardiovascular risk factors, and liver and kidney function in patients with type 2 diabetes.
    METHODS: PubMed, MEDLINE, Embase, Cochrane Library and CINAHL were searched for randomised controlled trials published between 2001 and 2021 that compared the ketogenic diet to a control diet for effects on glycaemic control, body weight, cardiovascular risk factors, liver and renal function markers in adults with type 2 diabetes for >14 days. Meta-analyses using fixed or random effects models were conducted.
    RESULTS: Nineteen reports from 11 randomised controlled trials were included. Compared to the control, the ketogenic diet showed no significant difference in changes in glycaemic control or body weight, but greater increases in HDL (standardised mean difference 0.19; 95%CI 0.02-0.37; I2 = 0 %; moderate-quality evidence) and greater reductions in triglycerides (standardised mean difference -0.41; 95%CI -0.64 to -0.18; I2 = 0 %; low-quality evidence).
    CONCLUSIONS: The ketogenic diet may improve lipid profiles but showed no additional benefits for glycaemic control or weight loss compared to control diets in type 2 diabetes patients over two years.
    Keywords:  Ketogenic diet; Low carbohydrate diet; Meta-analysis; Randomised trial; Type 2 diabetes
    DOI:  https://doi.org/10.1016/j.dsx.2023.102905
  7. Front Neurosci. 2023 ;17 1297984
    Ketone bodies mediate alterations in brain energy metabolism and biomarkers of Alzheimer's disease.
    Matin Ramezani, Malika Fernando, Shaun Eslick, Prita R Asih, Sina Shadfar, Ekanayaka M S Bandara, Heidi Hillebrandt, Silochna Meghwar, Maryam Shahriari, Pratishtha Chatterjee, Rohith Thota, Cintia B Dias, Manohar L Garg, Ralph N Martins.
      Alzheimer's disease (AD) is the most common form of dementia. AD is a progressive neurodegenerative disorder characterized by cognitive dysfunction, including learning and memory deficits, and behavioral changes. Neuropathology hallmarks of AD such as amyloid beta (Aβ) plaques and neurofibrillary tangles containing the neuron-specific protein tau is associated with changes in fluid biomarkers including Aβ, phosphorylated tau (p-tau)-181, p-tau 231, p-tau 217, glial fibrillary acidic protein (GFAP), and neurofilament light (NFL). Another pathological feature of AD is neural damage and hyperactivation of astrocytes, that can cause increased pro-inflammatory mediators and oxidative stress. In addition, reduced brain glucose metabolism and mitochondrial dysfunction appears up to 15 years before the onset of clinical AD symptoms. As glucose utilization is compromised in the brain of patients with AD, ketone bodies (KBs) may serve as an alternative source of energy. KBs are generated from the β-oxidation of fatty acids, which are enhanced following consumption of ketogenic diets with high fat, moderate protein, and low carbohydrate. KBs have been shown to cross the blood brain barrier to improve brain energy metabolism. This review comprehensively summarizes the current literature on how increasing KBs support brain energy metabolism. In addition, for the first time, this review discusses the effects of ketogenic diet on the putative AD biomarkers such as Aβ, tau (mainly p-tau 181), GFAP, and NFL, and discusses the role of KBs on neuroinflammation, oxidative stress, and mitochondrial metabolism.
    Keywords:  Alzheimer’s disease; brain energy fuel; circulating biomarkers; disease-modifying therapy; ketogenesis; ketogenic intervention; metabolic interaction
    DOI:  https://doi.org/10.3389/fnins.2023.1297984
  8. J Physiol. 2023 Nov 28.
    Loss of mitochondrial Ca2+ uptake protein 3 impairs skeletal muscle calcium handling and exercise capacity.
    Barbara Roman, Yusuf Mastoor, Yingfan Zhang, Dennis Gross, Danielle Springer, Chengyu Liu, Brian Glancy, Elizabeth Murphy.
      Mitochondrial calcium concentration ([Ca2+ ]m ) plays an essential role in bioenergetics, and loss of [Ca2+ ]m homeostasis can trigger diseases and cell death in numerous cell types. Ca2+ uptake into mitochondria occurs via the mitochondrial Ca2+ uniporter (MCU), which is regulated by three mitochondrial Ca2+ uptake (MICU) proteins localized in the intermembrane space, MICU1, 2, and 3. We generated a mouse model of systemic MICU3 ablation and examined its physiological role in skeletal muscle. We found that loss of MICU3 led to impaired exercise capacity. When the muscles were directly stimulated there was a decrease in time to fatigue. MICU3 ablation significantly increased the maximal force of the KO muscle and altered fibre type composition with an increase in the ratio of type IIb (low oxidative capacity) to type IIa (high oxidative capacity) fibres. Furthermore, MICU3-KO mitochondria have reduced uptake of Ca2+ and increased phosphorylation of pyruvate dehydrogenase, indicating that KO animals contain less Ca2+ in their mitochondria. Skeletal muscle from MICU3-KO mice exhibited lower net oxidation of NADH during electrically stimulated muscle contraction compared with wild-type. These data demonstrate that MICU3 plays a role in skeletal muscle physiology by setting the proper threshold for mitochondrial Ca2+ uptake, which is important for matching energy demand and supply in muscle. KEY POINTS: Mitochondrial calcium uptake is an important regulator of bioenergetics and cell death and is regulated by the mitochondrial calcium uniporter (MCU) and three calcium sensitive regulatory proteins (MICU1, 2 and 3). Loss of MICU3 leads to impaired exercise capacity and decreased time to skeletal muscle fatigue. Skeletal muscle from MICU3-KO mice exhibits a net oxidation of NADH during electrically stimulated muscle contractions, suggesting that MICU3 plays a role in skeletal muscle physiology by matching energy demand and supply.
    Keywords:  MICU3; calcium uptake; skeletal muscle
    DOI:  https://doi.org/10.1113/JP284894
  9. Diabetes Res Clin Pract. 2023 Nov 28. pii: S0168-8227(23)00794-5. [Epub ahead of print] 111031
    Ketone Production and Excretion Even During Mild Hyperglycemia and the Impact of Sodium-Glucose Co-transporter Inhibition in Type 1 Diabetes.
    Daniel Scarr, Erik Lovblom, Hongping Ye, Hongyan Liu, Abdulmohsen Bakhsh, Natasha J Verhoeff, Thomas M S Wolever, Patrick R Lawler, Kumar Sharma, David Z I Cherney, Bruce A Perkins.
       AIMS: We aimed to determine if ketone production and excretion are increased even at mild fasting hyperglycemia in type 1 diabetes (T1D) and if these are modified by ketoacidosis risk factors, including sodium-glucose co-transporter inhibition (SGLTi) and female sex.
    METHODS: In secondary analysis of an 8-week single-arm open-label trial of empagliflozin (NCT01392560) we evaluated ketone concentrations during extended fasting and clamped euglycemia (4-6 mmol/L) and mild hyperglycemia (9-11 mmol/L) prior to and after treatment. Plasma and urine beta-hydroxybutyrate (BHB) concentrations and fractional excretion were analyzed by metabolomic analysis.
    RESULTS: Forty participants (50% female), aged 24±5 years, HbA1c 8.0±0.9% (64±0.08 mmol/mol) with T1D duration of 17.5±7 years, were studied. Increased BHB production even during mild hyperglycemia (median urine 6.3[3.5-13.6] vs. 3.5[2.2-7.0] µmol/mmol creatinine during euglycemia, p<0.001) was compensated by increased fractional excretion (0.9% [0.3-1.6] vs. 0.4% [0.2-0.9], p<0.001). SGLTi increased production and attenuated the increased BHB fractional excretion (decreased to 0.3% during mild hyperglycemia, p<0.001), resulting in higher plasma concentrations (increased to 0.21 [0.05-0.40] mmol/L, p<0.001), particularly in females (interaction p<0.001).
    CONCLUSIONS: Even mild hyperglycemia is associated with greater ketone production, compensated by urinary excretion, in T1D. However, SGLTi exaggerates production and partially reduces compensatory excretion, particularly in women.
    DOI:  https://doi.org/10.1016/j.diabres.2023.111031
  10. Front Cell Dev Biol. 2023 ;11 1290046
    Mitochondrial quality control in health and cardiovascular diseases.
    Asli E Atici, Timothy R Crother, Magali Noval Rivas.
      Cardiovascular diseases (CVDs) are one of the primary causes of mortality worldwide. An optimal mitochondrial function is central to supplying tissues with high energy demand, such as the cardiovascular system. In addition to producing ATP as a power source, mitochondria are also heavily involved in adaptation to environmental stress and fine-tuning tissue functions. Mitochondrial quality control (MQC) through fission, fusion, mitophagy, and biogenesis ensures the clearance of dysfunctional mitochondria and preserves mitochondrial homeostasis in cardiovascular tissues. Furthermore, mitochondria generate reactive oxygen species (ROS), which trigger the production of pro-inflammatory cytokines and regulate cell survival. Mitochondrial dysfunction has been implicated in multiple CVDs, including ischemia-reperfusion (I/R), atherosclerosis, heart failure, cardiac hypertrophy, hypertension, diabetic and genetic cardiomyopathies, and Kawasaki Disease (KD). Thus, MQC is pivotal in promoting cardiovascular health. Here, we outline the mechanisms of MQC and discuss the current literature on mitochondrial adaptation in CVDs.
    Keywords:  ROS; cardiovascular disease; mitobiogenesis; mitochondria; mitochondrial dynamics; mitophagy
    DOI:  https://doi.org/10.3389/fcell.2023.1290046
  11. Biochimie. 2023 Nov 24. pii: S0300-9084(23)00310-3. [Epub ahead of print]
    Physiological 4-phenylbutyrate promotes mitochondrial biogenesis and metabolism in C2C12 myotubes.
    Caroline N Rivera, Carly E Smith, Lillian V Draper, Rachel M Watne, Andrew J Wommack, Roger A Vaughan.
      Type 2 diabetes is characterized by elevated circulating blood metabolites such as glucose, insulin, and branched chain amino acids (BCAA), which often coincide with reduced mitochondrial function. 4-Phenylbutyrate (PBA), an ammonia scavenger, has been shown to activate BCAA metabolism, resolve endoplasmic reticulum (ER) stress, and rescue BCAA-mediated insulin resistance. To determine the effect of PBA on the altered metabolic phenotype featured in type 2 diabetes, the present study investigated the effect of PBA on various metabolic parameters including mitochondrial metabolism and mitochondrial biogenesis. C2C12 myotubes were treated with PBA at 0.5 mM (representing physiologically attainable blood concentrations) or 10 mM (representing physiologically unattainable/proof-of-concept levels) for up to 24 h. Mitochondrial and glycolytic metabolism were assessed via oxygen consumption and extracellular acidification rate, respectively. Mitochondrial content, lipid content, and ER stress were measured by fluorescent staining. Metabolic gene expression was measured by qRT-PCR. Both doses of PBA increased expression of indicators of mitochondrial biogenesis, though only PBA at 0.5 mM increased mitochondrial function and content while 10 mM PBA reduced mitochondrial function and content. PBA at 0.5 mM also rescued reduced mitochondrial function during insulin resistance, though PBA also caused a reduced insulin stimulated pAkt expression during insulin resistance. PBA treatment also increased extracellular BCAA accumulation during insulin resistance despite unchanged pBCKDH expression. Taken together, PBA may increase mitochondrial biogenesis, content, and function in a dose-dependent fashion which may have implications for prevention or treatment of metabolic disease such as insulin resistance.
    Keywords:  Diabetes; Insulin resistance; Peroxisome proliferator-activated receptor alpha (Ppara); Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1); Skeletal muscle
    DOI:  https://doi.org/10.1016/j.biochi.2023.11.009
  12. J Physiol. 2023 Dec 02.
    Muscle glycogen depletion: a weak-link rendering muscle cells prone to potassium-induced fatigue?
    Jeppe F Vigh-Larsen.
      
    Keywords:  carbohydrate; excitability; intermittent exercise; metabolism
    DOI:  https://doi.org/10.1113/JP285818
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