The New Ketone Alphabet Soup: BHB, HCA, and HDAC

Hartman, Adam L.; Rho, Jong M.

doi:10.5698/1535-7597-14.6.355

Cited by 10 publications

(6 citation statements)

References 21 publications

(27 reference statements)

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“…Indirect downregulation of AMPK was accompanied by the mentioned above increase in OXCT1 expression, known to be involved in AMPK signaling inhibition [ 50 ], βHb oxidation [ 30 ], as well as increasing MCF7 cell proliferation [ 51 ]. Although our findings contradict the conventional view of βHb as an HDAC1 inhibitor [ 52 ], analysis of clinical studies using the cBioportal database revealed a highly positive correlation between alterations in the OXCT1 gene and HDAC11 expression. This correlation suggests that when OXCT1 expression is altered by βHb treatment, it may be responsible for the increase in HDAC1 levels.…”

Section: Discussioncontrasting

confidence: 99%

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells

Fulman-Levy,

Cohen-Harazi,

Levi

et al. 2024

Cancer Metab

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Background The ketogenic diet (KD), based on high fat (over 70% of daily calories), low carbohydrate, and adequate protein intake, has become popular due to its potential therapeutic benefits for several diseases including cancer. Under KD and starvation conditions, the lack of carbohydrates promotes the production of ketone bodies (KB) from fats by the liver as an alternative source of metabolic energy. KD and starvation may affect the metabolism in cancer cells, as well as tumor characteristics. The aim of this study is to evaluate the effect of KD conditions on a wide variety of aspects of breast cancer cells in vitro. Methods Using two cancer and one non-cancer breast cell line, we evaluate the effect of β-hydroxybutyrate (βHb) treatment on cell growth, survival, proliferation, colony formation, and migration. We also assess the effect of KB on metabolic profile of the cells. Using RNAseq analysis, we elucidate the effect of βHb on the gene expression profile. Results Significant effects were observed following treatment by βHb which include effects on viability, proliferation, and colony formation of MCF7 cells, and different effects on colony formation of MDA-MB-231 cells, with no such effects on non-cancer HB2 cells. We found no changes in glucose intake or lactate output following βHb treatment as measured by LC-MS, but an increase in reactive oxygen species (ROS) level was detected. RNAseq analysis demonstrated significant changes in genes involved in lipid metabolism, cancer, and oxidative phosphorylation. Conclusions Based on our results, we conclude that differential response of cancer cell lines to βHb treatment, as alternative energy source or signal to alter lipid metabolism and oncogenicity, supports the need for a personalized approach to breast cancer patient treatment.

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Section: Discussioncontrasting

confidence: 99%

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells

Fulman-Levy,

Cohen-Harazi,

Levi

et al. 2024

Cancer Metab

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“…Epileptic seizures triggered the deacetylation of histone H4 at the GluR2 locus (Huang et al, 2002;Tsankova et al, 2004), which is associated with increased neuronal excitability and the initiation of epileptogenesis (Tanaka et al, 2000). Experimental findings support the idea that KD, as well as ketone bodies formed from fatty acid oxidation, such as BHB, acetoacetate (ACA), and acetone may have antiepileptogenic potential by inhibiting HDACs (Boison and Rho, 2020;Hartman and Rho, 2014;Hauser et al, 2018;Simeone et al, 2017b;Tanaka et al, 2000). Thus, inhibition of HDAC activity by chronic administration of butyrate retarded the development of limbic epileptogenesis and prevented epileptogenic mossy fiber axonal sprouting in a mouse hippocampal kindling model of TLE (Reddy et al, 2018).…”

Section: Histone Acetylationmentioning

confidence: 63%

“…Histone modifications such as acetylation and deacetylation are essential parts of gene regulation and are mediated by the enzymes histone acetyltransferase and histone deacetylase (HDAC), respectively (Simeone et al, 2017a). Altered histone acetylation has been noted in epilepsy patients as well as in animal models of epilepsy and is thought to be associated with epileptogenesis (Boison and Rho, 2020;Hartman and Rho, 2014;Hauser et al, 2018). Epileptic seizures triggered the deacetylation of histone H4 at the GluR2 locus (Huang et al, 2002;Tsankova et al, 2004), which is associated with increased neuronal excitability and the initiation of epileptogenesis (Tanaka et al, 2000).…”

Section: Histone Acetylationmentioning

confidence: 99%

Ketogenic diet, neuroprotection, and antiepileptogenesis

Murugan

Boison

2020

Epilepsy Research

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“…Interest in ketones has surged in the recent years. Illustrated by the sheer abundance of reviews and perspective articles on the potential benefits of ketosis, βOHB is considered as a potential mediator of the putative fasting-related health benefits ( 2 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ). Common to all reviews is the prominent portrayal of βOHB as a potent HDAC inhibitor influencing gene expression, a notion originating from work by Shimazu et al in kidney and HEK293 cells ( 24 ).…”

Section: Discussionmentioning

confidence: 99%

“…In addition to serving as fuel in tissues such as the brain, heart, and skeletal muscle, recent research has unveiled that βOHB may also serve as a direct signaling molecule. By activating specific signaling pathways, βOHB may not only have an important regulatory role in the metabolic response to fasting but may also potentially mediate some of the beneficial health effects of fasting (2,12,13,14,15,16,17,18,19,20,21,22,23). Evidence has been presented that βOHB may regulate gene expression via epigenetic mechanisms.…”

Section: Introductionmentioning

confidence: 99%

RNA sequencing reveals niche gene expression effects of beta-hydroxybutyrate in primary myotubes

et al. 2021

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Various forms of fasting and ketogenic diet have shown promise in (pre-)clinical studies to normalize body weight, improve metabolic health, and protect against disease. Recent studies suggest that β-hydroxybutyrate (βOHB), a fasting-characteristic ketone body, potentially acts as a signaling molecule mediating its beneficial effects via histone deacetylase inhibition. Here, we have investigated whether βOHB, in comparison to the well-established histone deacetylase inhibitor butyrate, influences cellular differentiation and gene expression. In various cell lines and primary cell types, millimolar concentrations of βOHB did not alter differentiation in vitro, as determined by gene expression and histological assessment, whereas equimolar concentrations of butyrate consistently impaired differentiation. RNA sequencing revealed that unlike butyrate, βOHB minimally impacted gene expression in primary adipocytes, macrophages, and hepatocytes. However, in myocytes, βOHB up-regulated genes involved in the TCA cycle and oxidative phosphorylation, while down-regulating genes belonging to cytokine and chemokine signal transduction. Overall, our data do not support the notion that βOHB serves as a powerful signaling molecule regulating gene expression but suggest that βOHB may act as a niche signaling molecule in myocytes.

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The New Ketone Alphabet Soup: BHB, HCA, and HDAC

Cited by 10 publications

References 21 publications

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells

Metabolic alterations and cellular responses to β-Hydroxybutyrate treatment in breast cancer cells

Ketogenic diet, neuroprotection, and antiepileptogenesis

RNA sequencing reveals niche gene expression effects of beta-hydroxybutyrate in primary myotubes

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