Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development

Zhang, Huafeng; Tang, Ke; Ma, Jingwei; Zhou, Li; Liu, Jincheng; Zeng, Liping; Zhu, Liyan; Xu, Pingwei; Chen, Jie; Wei, Keke; Liang, Xiaoyu; Lv, Jiadi; Xie, Jing; Liu, Yuying; Wan, Yonghong; Huang, Bo

doi:10.1038/s41556-019-0440-0

Cited by 109 publications

(90 citation statements)

References 28 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Ketogenesis takes place in the mitochondria of perivenous hepatocytes, and marginally in astrocytes of the brain, in Lgr5 + intestinal stem cells and in T-cells [8,[13][14][15]. Hepatic production of ketone bodies is a physiological response to prolonged exercise, starving or reduced carbohydrate nutritional intake, but is also a pathological consequence of beta-cells failing to secrete insulin in diabetes.…”

Section: Anabolism and Catabolism Of Ketone Bodiesmentioning

confidence: 99%

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

et al. 2020

View full text Add to dashboard Cite

Ketone bodies (KBs), comprising β-hydroxybutyrate, acetoacetate and acetone, are a set of fuel molecules serving as an alternative energy source to glucose. KBs are mainly produced by the liver from fatty acids during periods of fasting, and prolonged or intense physical activity. In diabetes, mainly type-1, ketoacidosis is the pathological response to glucose malabsorption. Endogenous production of ketone bodies is promoted by consumption of a ketogenic diet (KD), a diet virtually devoid of carbohydrates. Despite its recently widespread use, the systemic impact of KD is only partially understood, and ranges from physiologically beneficial outcomes in particular circumstances to potentially harmful effects. Here, we firstly review ketone body metabolism and molecular signaling, to then link the understanding of ketone bodies’ biochemistry to controversies regarding their putative or proven medical benefits. We overview the physiological consequences of ketone bodies’ consumption, focusing on (i) KB-induced histone post-translational modifications, particularly β-hydroxybutyrylation and acetylation, which appears to be the core epigenetic mechanisms of activity of β-hydroxybutyrate to modulate inflammation; (ii) inflammatory responses to a KD; (iii) proven benefits of the KD in the context of neuronal disease and cancer; and (iv) consequences of the KD’s application on cardiovascular health and on physical performance.

show abstract

Section: Anabolism and Catabolism Of Ketone Bodiesmentioning

confidence: 99%

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In addition, β-hydroxybutyrate (β-HB) may mediate the effect of a ketogenic diet [113,114], intermittent fasting [115] or exercise [116] on healthspan extension or neuroregeneration because of its anti-inflammation [117], inhibition of vascular cell senescence [118] or immune activation by the formation and maintenance of CD8 + memory T cells [119]. It would be interesting to test the action of β-HB on healthy ageing and chronic diseases in preclinical and clinical research.…”

Section: Adipocytesmentioning

confidence: 99%

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

Song

2020

Cells

111

View full text Add to dashboard Cite

Senescent cells are generally characterized by permanent cell cycle arrest, metabolic alteration and activation, and apoptotic resistance in multiple organs due to various stressors. Excessive accumulation of senescent cells in numerous tissues leads to multiple chronic diseases, tissue dysfunction, age-related diseases and organ ageing. Immune cells can remove senescent cells. Immunaging or impaired innate and adaptive immune responses by senescent cells result in persistent accumulation of various senescent cells. Although senolytics—drugs that selectively remove senescent cells by inducing their apoptosis—are recent hot topics and are making significant research progress, senescence immunotherapies using immune cell-mediated clearance of senescent cells are emerging and promising strategies to fight ageing and multiple chronic diseases. This short review provides an overview of the research progress to date concerning senescent cell-caused chronic diseases and tissue ageing, as well as the regulation of senescence by small-molecule drugs in clinical trials and different roles and regulation of immune cells in the elimination of senescent cells. Mounting evidence indicates that immunotherapy targeting senescent cells combats ageing and chronic diseases and subsequently extends the healthy lifespan.

show abstract

“…This is the first time that histone Kbhb was identified as a new way of epigenetic regulation that regulates cellular physiology [47]. Ketogenesis also represents a metabolic pathway required for the development of memory CD8+ T cells where BHB promotes β-hydroxybutyrylation of Lys9 in H3 (H3K9bhb) and this is associated to upregulation in the gene expression of Foxo1 and Ppargc1a, which cooperatively upregulate Pck1 expression [50]. Furthermore, BHB regulates the inflammasome and the expression of associated inflammatory genes through histone Kbhb, reducing inflammatory responses and blood pressure [51].…”

Section: Histone β-Hydroxybutyrylationmentioning

confidence: 99%

“…Interestingly, a low-calorie intake is the only maneuver that consistently increased lifespan in all species tested and it is thought that fasting is a key contributor to this effect. Fasting also increases 3-hydroxybutyric acid levels, increasing the histone β-hydroxybutyrylation of, for example, the Ppargc1a gene encoding PGC-1α [50], which is a key nephroprotective molecule [135,[165][166][167]. Finally, despite the description of the association of some epigenetic modifications of specific features, and even to specific molecules involved in DKD, there is an insufficient understanding on the cause-and-effect relationship between these specific molecular changes and the overall impact of targeting epigenetic modifications in vivo.…”

Section: Summary and Future Perspectivesmentioning

confidence: 99%

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

Martínez-Moreno

Fontecha‐Barriuso

Martín‐Sánchez

et al. 2020

IJMS

View full text Add to dashboard Cite

Diabetic kidney disease is one of the fastest growing causes of death worldwide. Epigenetic regulators control gene expression and are potential therapeutic targets. There is functional interventional evidence for a role of DNA methylation and the histone post-translational modifications—histone methylation, acetylation and crotonylation—in the pathogenesis of kidney disease, including diabetic kidney disease. Readers of epigenetic marks, such as bromodomain and extra terminal (BET) proteins, are also therapeutic targets. Thus, the BD2 selective BET inhibitor apabetalone was the first epigenetic regulator to undergo phase-3 clinical trials in diabetic kidney disease with an endpoint of kidney function. The direct therapeutic modulation of epigenetic features is possible through pharmacological modulators of the specific enzymes involved and through the therapeutic use of the required substrates. Of further interest is the characterization of potential indirect effects of nephroprotective drugs on epigenetic regulation. Thus, SGLT2 inhibitors increase the circulating and tissue levels of β-hydroxybutyrate, a molecule that generates a specific histone modification, β-hydroxybutyrylation, which has been associated with the beneficial health effects of fasting. To what extent this impact on epigenetic regulation may underlie or contribute to the so-far unclear molecular mechanisms of cardio- and nephroprotection offered by SGLT2 inhibitors merits further in-depth studies.

show abstract

Ketogenesis-generated β-hydroxybutyrate is an epigenetic regulator of CD8+ T-cell memory development

Cited by 109 publications

References 28 publications

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

Modulation of Cellular Biochemistry, Epigenetics and Metabolomics by Ketone Bodies. Implications of the Ketogenic Diet in the Physiology of the Organism and Pathological States

Immune Clearance of Senescent Cells to Combat Ageing and Chronic Diseases

Epigenetic Modifiers as Potential Therapeutic Targets in Diabetic Kidney Disease

Contact Info

Product

Resources

About