Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta—Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons

Dabke, Partha

doi:10.3390/nu12082379

Cited by 30 publications

(30 citation statements)

References 87 publications

(116 reference statements)

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“…We recently demonstrated that sirtuins (a group of NAD+-dependent enzymes) and the mitochondrial respiratory chain complexes were upregulated in HT22 neurons under C10- and ßHB-incubation [ 39 ]. Lipids serve as energy substrates in the CNS (reviewed in [ 2 ]) and phospholipids such as PE and CL are crucial for the efficient functioning of the respiratory chain and maintaining the mitochondrial membrane potential [ 8 , 40 ].…”

Section: Discussionmentioning

confidence: 99%

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Ketogenic Diet: Impact on Cellular Lipids in Hippocampal Murine Neurons

2020

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Background: The mechanism of action of the ketogenic diet (KD), an effective treatment for pharmacotherapy refractory epilepsy, is not fully elucidated. The present study examined the effects of two metabolites accumulating under KD—beta-hydroxybutyrate (ßHB) and decanoic acid (C10) in hippocampal murine (HT22) neurons. Methods: A mouse HT22 hippocampal neuronal cell line was used in the present study. Cellular lipids were analyzed in cell cultures incubated with high (standard) versus low glucose supplemented with ßHB or C10. Cellular cholesterol was analyzed using HPLC, while phospholipids and sphingomyelin (SM) were analyzed using HPTLC. Results: HT22 cells showed higher cholesterol, but lower SM levels in the low glucose group without supplements as compared to the high glucose groups. While cellular cholesterol was reduced in both ßHB- and C10-incubated cells, phospholipids were significantly higher in C10-incubated neurons. Ratios of individual phospholipids to cholesterol were significantly higher in ßHB- and C10-incubated neurons as compared to controls. Conclusion: Changes in the ratios of individual phospholipids to cholesterol in HT22 neurons suggest a possible alteration in the composition of the plasma membrane and organelle membranes, which may provide insight into the working mechanism of KD metabolites ßHB and C10.

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Section: Discussionmentioning

confidence: 99%

“…All red arrows depict the effects of ßHB, and all blue arrows depict the effects of C10. Thin arrows show already published data (adapted from [ 39 ]). Solid thick arrows show the effects of ßHB and C10 on absolute quantities of the depicted cellular lipids.…”

Section: Figurementioning

confidence: 99%

Ketogenic Diet: Impact on Cellular Lipids in Hippocampal Murine Neurons

2020

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“…A ketogenic diet is neuroprotective through reduction of ROS levels, by increasing mitochondrial uncoupling protein levels and activity [ 436 ], as well as by increasing oxidation of NADH and enhancing mitochondrial respiration [ 437 ]. This diet results in increased SIRT1 levels in mice hippocampal neurons [ 438 ]. Ketosis may also activate SIRT1 due to an increased NAD+/NADH ratio, which in turn can promote autophagy in the brain [ 439 ].…”

Section: The Role Of Sirtuins In Metabolic Tissuesmentioning

confidence: 99%

Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review

Maissan

Mooij

Barberis

2021

Biology

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Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins’ activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.

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“…IF leads to ketogenic metabolism, increasing β-hydroxybutyrate levels in serum and CSF [ 162 ]. Interestingly, β-hydroxybutyrate protects against Aβ toxicity [ 163 , 164 ] and protects hippocampal murine neurons [ 165 , 166 ]. Whereas previous studies have reported no significant effects of IF on neuroinflammation, synaptic plasticity or cognitive function in 6-month 5xFAD mice [ 167 ], it has also been shown that IF restores aquaporin-4 polarity, reduces SP deposition and ameliorates cognitive dysfunction in APP/PS1 mice [ 168 ].…”

Section: Diet Inflammation and Gut Microbiota In Ad Modelsmentioning

confidence: 99%

Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models

et al. 2021

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Alzheimer’s disease (AD) is the most common cause of dementia. Epidemiological studies show the association between AD and type 2 diabetes (T2DM), although the mechanisms are not fully understood. Dietary habits and lifestyle, that are risk factors in both diseases, strongly modulate gut microbiota composition. Also, the brain-gut axis plays a relevant role in AD, diabetes and inflammation, through products of bacterial metabolism, like short-chain fatty acids. We provide a comprehensive review of current literature on the relation between dysbiosis, altered inflammatory cytokines profile and microglia in preclinical models of AD, T2DM and models that reproduce both diseases as commonly observed in the clinic. Increased proinflammatory cytokines, such as IL-1β and TNF-α, are widely detected. Microbiome analysis shows alterations in Actinobacteria, Bacteroidetes or Firmicutes phyla, among others. Altered α- and β-diversity is observed in mice depending on genotype, gender and age; therefore, alterations in bacteria taxa highly depend on the models and approaches. We also review the use of pre- and probiotic supplements, that by favoring a healthy microbiome ameliorate AD and T2DM pathologies. Whereas extensive studies have been carried out, further research would be necessary to fully understand the relation between diet, microbiome and inflammation in AD and T2DM.

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Mechanism of Action of Ketogenic Diet Treatment: Impact of Decanoic Acid and Beta—Hydroxybutyrate on Sirtuins and Energy Metabolism in Hippocampal Murine Neurons

Cited by 30 publications

References 87 publications

Ketogenic Diet: Impact on Cellular Lipids in Hippocampal Murine Neurons

Ketogenic Diet: Impact on Cellular Lipids in Hippocampal Murine Neurons

Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review

Alzheimer’s Disease and Diabetes: Role of Diet, Microbiota and Inflammation in Preclinical Models

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