Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes

Castonguay, Zachary; Auger, Christopher; Thomas, Sean C.; Chahma, M’hamed; Appanna, Vasu D.

doi:10.1016/j.bbrc.2014.10.071

Cited by 33 publications

(24 citation statements)

References 30 publications

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“…Of particular interest for this study, phosphorylation of Tyr238 on LDH has been shown to promote nuclear translocation. In this scenario, locally produced lactate inhibits HDACs and increases gene transcription . Growing evidence thus suggests that metabolic intermediates and byproducts, such as lactate, can directly link cellular metabolism to functions such as cell proliferation and survival through altered gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…In this scenario, locally produced lactate inhibits HDACs and increases gene transcription. (79,80) Growing evidence thus suggests that metabolic intermediates and byproducts, such as lactate, can directly link cellular metabolism to functions such as cell proliferation and survival through altered gene transcription. Therefore, it is possible that the loss of MCT4 contributes to disc degeneration through a cumulative effect on the transcriptional program in NP cells.…”

Section: Discussionmentioning

confidence: 99%

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Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Silagi

Novais

Bisetto

et al. 2019

Journal of Bone and Mineral Research

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Maintenance of glycolytic metabolism is postulated to be required for health of the spinal column. In the hypoxic tissues of the intervertebral disc and glycolytic cells of vertebral bone, glucose is metabolized into pyruvate for ATP generation and reduced to lactate to sustain redox balance. The rise in intracellular H+/lactate concentrations are balanced by plasma‐membrane monocarboxylate transporters (MCTs). Using MCT4 null mice and human tissue samples, complemented with genetic and metabolic approaches, we determine that H+/lactate efflux is critical for maintenance of disc and vertebral bone health. Mechanistically, MCT4 maintains glycolytic and tricarboxylic acid (TCA) cycle flux and intracellular pH homeostasis in the nucleus pulposus compartment of the disc, where hypoxia‐inducible factor 1α (HIF‐1α) directly activates an intronic enhancer in SLC16A3. Ultimately, our results provide support for research into lactate as a diagnostic biomarker for chronic, painful, disc degeneration. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Silagi

Novais

Bisetto

et al. 2019

Journal of Bone and Mineral Research

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“…Nuclear LDH binds to DNA [56] and interacts with DNA polymerases /, d and e, stimulating DNA synthesis and post-UV radiation DNA repair [42]. Nuclear LDH physically associates with sirtuin 1 [57], with LDH-produced NAD + [ 2 5 _ T D $ D I F F ] increasing sirtuin 1 activity.…”

Section: Enolasementioning

confidence: 99%

Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription

Boukouris

Zervopoulos

Michelakis

2016

Trends in Biochemical Sciences

243

206

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“…*P < 0.05; **P < 0.01; † P < 0.005; † † P < 0.001. (15,16). The ratio of BHB to AcAc is governed by the cellular NADH/NAD + ratio (Fig.…”

Section: Backgrounds (>10 Generations) Hippocampal Gene Expression Pmentioning

confidence: 99%

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

Benjamin

Pilarowski

Carosso

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

120

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Kabuki syndrome is a Mendelian intellectual disability syndrome caused by mutations in either of two genes (KMT2D and KDM6A) involved in chromatin accessibility. We previously showed that an agent that promotes chromatin opening, the histone deacetylase inhibitor (HDACi) AR-42, ameliorates the deficiency of adult neurogenesis in the granule cell layer of the dentate gyrus and rescues hippocampal memory defects in a mouse model of Kabuki syndrome (Kmt2d+/βGeo). Unlike a drug, a dietary intervention could be quickly transitioned to the clinic. Therefore, we have explored whether treatment with a ketogenic diet could lead to a similar rescue through increased amounts of beta-hydroxybutyrate, an endogenous HDACi. Here, we report that a ketogenic diet in Kmt2d+/βGeo mice modulates H3ac and H3K4me3 in the granule cell layer, with concomitant rescue of both the neurogenesis defect and hippocampal memory abnormalities seen in Kmt2d+/βGeo mice; similar effects on neurogenesis were observed on exogenous administration of beta-hydroxybutyrate. These data suggest that dietary modulation of epigenetic modifications through elevation of beta-hydroxybutyrate may provide a feasible strategy to treat the intellectual disability seen in Kabuki syndrome and related disorders.

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Nuclear lactate dehydrogenase modulates histone modification in human hepatocytes

Cited by 33 publications

References 30 publications

Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Lactate Efflux From Intervertebral Disc Cells Is Required for Maintenance of Spine Health

Metabolic Enzymes Moonlighting in the Nucleus: Metabolic Regulation of Gene Transcription

A ketogenic diet rescues hippocampal memory defects in a mouse model of Kabuki syndrome

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