PHGDH supports liver ceramide synthesis and sustains lipid homeostasis

AbstractBackgroundD-3-phosphoglycerate dehydrogenase (PHGDH), which encodes the first enzyme in serine biosynthesis, is overexpressed in human cancers and has been proposed as a drug target. However, whether PHGDH is critical for the proliferation or homeostasis of tissues following the postnatal period is unknown.MethodsTo study PHGDH inhibition in adult animals, we developed a knock-in mouse model harboring a PHGDH shRNA under the control of a doxycycline-inducible promoter. With this model, PHGDH depletion can be globally induced in adult animals, while sparing the brain due to poor doxycycline delivery.ResultsWe found that PHGDH depletion is well tolerated and no overt phenotypes were observed in multiple highly proliferative cell compartments. Further, despite detectable knockdown, liver and pancreatic function were normal. Interestingly, diminished PHGDH expression in the liver reduced serine and ceramide levels without increasing the levels of deoxysphingolipids. Further, liver triacylglycerol profiles were altered, with an accumulation of longer chain, polyunsaturated tails upon PHGDH knockdown.ConclusionsThese results suggest that dietary serine is adequate to support the function of healthy, adult murine tissues, but PHGDH-derived serine supports liver ceramide synthesis and sustains general lipid homeostasis.

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L-Serine regulates the activities of microglial cells that express very low level of 3-phosphoglycerate dehydrogenase, an enzyme forL-serine biosynthesis

Journal of Neuroscience Research ◽

10.1002/jnr.1090 ◽

2001 ◽

Vol 64 (4) ◽

pp. 392-401 ◽

Cited By ~ 19

Author(s):

Hiroki Sugishita ◽

Yasuhide Kuwabara ◽

Kazuko Toku ◽

Lisa Doi ◽

Lihua Yang ◽

...

Keyword(s):

Microglial Cells ◽

Low Level ◽

Phosphoglycerate Dehydrogenase ◽

Serine Biosynthesis

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Bidirectional Electrical Coupling Between Inspiratory Motoneurons in the Newborn Mouse Nucleus Ambiguus

Journal of Neurophysiology ◽

10.1152/jn.1997.78.6.3508 ◽

1997 ◽

Vol 78 (6) ◽

pp. 3508-3510 ◽

Cited By ~ 43

Author(s):

Jens C. Rekling ◽

Jack L. Feldman

Keyword(s):

Brain Stem ◽

Impulse Activity ◽

Electrical Coupling ◽

Postnatal Period ◽

The Other ◽

Nucleus Ambiguus ◽

Newborn Mouse ◽

Coupling Ratio ◽

Newborn Mice ◽

The Brain

Rekling, Jens C. and Jack L. Feldman. Bidirectional electrical coupling between inspiratory motoneurons in the newborn mouse nucleus ambiguus. J. Neurophysiol. 78: 3508–3510, 1997. Some spinal and brain stem motoneurons are electrically coupled in the early postnatal period. To test whether respiratory motoneurons in the brain stem are electrically coupled, we performed single and dual whole cell patch recordings from presumptive motoneurons in the nucleus ambiguus in a rhythmically active brain stem slice from newborn mice. Two of eight (25%) biocytin-injected neurons showed dye-coupling and 4 of 11 (36%) of intracellularly recorded pairs of neurons showed evidence of bidirectional electrical coupling. Impulse activity in one cell elicited small spikelets in the other and hyperpolarization of one cell led to hyperpolarization of the other with a coupling ratio (Δ V 2:Δ V 1) of 0.03–0.14. We conclude that inspiratory ambiguus motoneurons in the newborn mouse brain stem are bidirectionally electrically coupled, which may serve to transmit or coordinate signals, chemical or electrical.

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3-Phosphoglycerate Dehydrogenase, a Key Enzyme forl-Serine Biosynthesis, Is Preferentially Expressed in the Radial Glia/Astrocyte Lineage and Olfactory Ensheathing Glia in the Mouse Brain

Journal of Neuroscience ◽

10.1523/jneurosci.21-19-07691.2001 ◽

2001 ◽

Vol 21 (19) ◽

pp. 7691-7704 ◽

Cited By ~ 129

Author(s):

Miwako Yamasaki ◽

Keiko Yamada ◽

Shigeki Furuya ◽

Junya Mitoma ◽

Yoshio Hirabayashi ◽

...

Keyword(s):

Mouse Brain ◽

Radial Glia ◽

Key Enzyme ◽

Phosphoglycerate Dehydrogenase ◽

Olfactory Ensheathing Glia ◽

Serine Biosynthesis

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Study of fetal and postnatal morphological development of the brain sulci

Journal of Neurosurgery Pediatrics ◽

10.3171/2012.9.peds12122 ◽

2013 ◽

Vol 11 (1) ◽

pp. 1-11 ◽

Cited By ~ 20

Author(s):

Koshiro Nishikuni ◽

Guilherme Carvalhal Ribas

Keyword(s):

Morphological Changes ◽

Fetal Brain ◽

Postnatal Period ◽

Postnatal Life ◽

Morphological Development ◽

Fetal Life ◽

Brain Hemispheres ◽

Collateral Sulcus ◽

Fetal Brain Development ◽

The Brain

Object The surface of the developing fetal brain undergoes significant morphological changes during fetal growth. The purpose of this study was to evaluate the morphological development of the brain sulci from the fetal to the early postnatal period. Methods Two hundred fourteen brain hemispheres from 107 human brain specimens were examined to evaluate the timing of sulcal formation, from its appearance to its complete development. These brains were obtained from cadavers ranging in age from 12 weeks of gestation to 8 months of postnatal life. Results The order of appearance of the cerebral sulci, and the number and percentages of specimens found in this study were as follows: longitudinal cerebral fissure at 12 weeks (10/10, 100%); callosal sulcus at 12 weeks (10/10, 100%); hippocampal sulcus at 15 weeks (7/10, 70%); lateral sulcus at 17 weeks (20/22, 90.9%); circular insular sulcus at 17 weeks (18/22, 81.8%); olfactory sulcus at 17 weeks (18/22, 81.8%); calcarine sulcus at 17 weeks (14/22, 63.6%); parietooccipital sulcus at 17 weeks (11/22, 50%); cingulate sulcus at 19 weeks (16/20, 80%); central sulcus at 21 weeks (22/38, 57.9%); orbital sulcus at 22 weeks (9/16, 56.2%); lunate sulcus at 24 ± 2 weeks (12/16, 75%); collateral sulcus at 24 ± 2 weeks (8/16, 50%); superior frontal sulcus at 25 ± 2 weeks (5/6, 83.3%); rhinal sulcus at 25 ± 2 weeks (3/6, 50%); precentral sulcus at 26 ± 3 weeks (2/4, 50%); postcentral sulcus at 26 ± 3 weeks (2/4, 50%); superior temporal sulcus at 26 ± 3 weeks (2/4, 50%); central insular sulcus at 29 ± 2 weeks (4/4, 100%); intraparietal sulcus at 29 ± 2 weeks (2/4, 50%); paraolfactory sulcus at 29 ± 2 weeks (2/4, 50%); inferior frontal sulcus at 30 ± 3 weeks (2/4, 50%); transverse occipital sulcus at 30 ± 3 weeks (2/4, 50%); occipitotemporal sulcus at 30 ± 3 weeks (2/4, 50%); marginal branch of the cingulate sulcus at 30 ± 3 weeks (2/4, 50%); paracentral sulcus at 30 ± 3 weeks (2/4, 50%); subparietal sulcus at 30 ± 3 weeks (2/4, 50%); inferior temporal sulcus at 31 ± 3 weeks (3/6, 50%); transverse temporal sulcus at 33 ± 3 weeks (6/8, 75%); and secondary sulcus at 38 ± 3 weeks (2/4, 50%). Conclusions The brain is subjected to considerable morphological changes throughout gestation. During fetal brain development the cortex begins to fold in, thereby increasing the cortical surface. All primary sulci are formed during fetal life. The appearance of each sulcus follows a characteristic timing pattern, which may be used as one of the reliable guides pertinent to gestational age and normal fetal development.

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Serine metabolism in the brain regulates starvation-induced sleep suppression in Drosophila melanogaster

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1719033115 ◽

2018 ◽

Vol 115 (27) ◽

pp. 7129-7134 ◽

Cited By ~ 9

Author(s):

Jun Young Sonn ◽

Jongbin Lee ◽

Min Kyung Sung ◽

Hwajung Ri ◽

Jung Kyoon Choi ◽

...

Keyword(s):

Drosophila Melanogaster ◽

Hypomorphic Mutation ◽

Cholinergic Signaling ◽

Sleep Behaviors ◽

Metabolizing Enzyme ◽

Rate Limiting ◽

The Brain ◽

Serine Biosynthesis ◽

Serine Metabolism ◽

Genetic Mutants

Sleep and metabolism are physiologically and behaviorally intertwined; however, the molecular basis for their interaction remains poorly understood. Here, we identified a serine metabolic pathway as a key mediator for starvation-induced sleep suppression. Transcriptome analyses revealed that enzymes involved in serine biosynthesis were induced upon starvation in Drosophila melanogaster brains. Genetic mutants of astray (aay), a fly homolog of the rate-limiting phosphoserine phosphatase in serine biosynthesis, displayed reduced starvation-induced sleep suppression. In contrast, a hypomorphic mutation in a serine/threonine-metabolizing enzyme, serine/threonine dehydratase (stdh), exaggerated starvation-induced sleep suppression. Analyses of double mutants indicated that aay and stdh act on the same genetic pathway to titrate serine levels in the head as well as to adjust starvation-induced sleep behaviors. RNA interference-mediated depletion of aay expression in neurons, using cholinergic Gal4 drivers, phenocopied aay mutants, while a nicotinic acetylcholine receptor antagonist selectively rescued the exaggerated starvation-induced sleep suppression in stdh mutants. Taken together, these data demonstrate that neural serine metabolism controls sleep during starvation, possibly via cholinergic signaling. We propose that animals have evolved a sleep-regulatory mechanism that reprograms amino acid metabolism for adaptive sleep behaviors in response to metabolic needs.

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Neurogenesis and brain aging

Reviews in the Neurosciences ◽

10.1515/revneuro-2018-0084 ◽

2019 ◽

Vol 30 (6) ◽

pp. 573-580 ◽

Cited By ~ 7

Author(s):

Nickolay K. Isaev ◽

Elena V. Stelmashook ◽

Elisaveta E. Genrikhs

Keyword(s):

Brain Aging ◽

Werner Syndrome ◽

Accelerated Aging ◽

Normal Aging ◽

Postnatal Period ◽

Human Aging ◽

Distinctive Features ◽

Progeria Syndrome ◽

Hutchinson Gilford Progeria Syndrome ◽

The Brain

AbstractHuman aging affects the entire organism, but aging of the brain must undoubtedly be different from that of all other organs, as neurons are highly differentiated postmitotic cells, for the majority of which the lifespan in the postnatal period is equal to the lifespan of the entire organism. In this work, we examine the distinctive features of brain aging and neurogenesis during normal aging, pathological aging (Alzheimer’s disease), and accelerated aging (Hutchinson-Gilford progeria syndrome and Werner syndrome).

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Correction for Mullarky et al., Identification of a small molecule inhibitor of 3-phosphoglycerate dehydrogenase to target serine biosynthesis in cancers

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1602228113 ◽

2016 ◽

Vol 113 (11) ◽

pp. E1585-E1585 ◽

Cited By ~ 2

Keyword(s):

Small Molecule ◽

Small Molecule Inhibitor ◽

Molecule Inhibitor ◽

Phosphoglycerate Dehydrogenase ◽

Serine Biosynthesis

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Preconditioning and Postinsult Therapies for Perinatal Hypoxic–Ischemic Injury at Term

Anesthesiology ◽

10.1097/aln.0b013e3181dc1b84 ◽

2010 ◽

Vol 113 (1) ◽

pp. 233-249 ◽

Cited By ~ 38

Author(s):

Robert D. Sanders ◽

Helen J. Manning ◽

Nicola J. Robertson ◽

Daqing Ma ◽

A. David Edwards ◽

...

Keyword(s):

Perinatal Period ◽

Rapid Identification ◽

Postnatal Period ◽

Hypoxic Ischemic Encephalopathy ◽

Current Status ◽

Neuroprotective Agents ◽

Period 2 ◽

Neuroprotective Strategies ◽

The Brain ◽

Ischemic Encephalopathy

Perinatal hypoxic-ischemic encephalopathy can be a devastating complication of childbirth. Herein, the authors review the pathophysiology of hypoxic-ischemic encephalopathy and the current status of neuroprotective strategies to ameliorate the injury centering on four themes: (1) monitoring in the perinatal period, (2) rapid identification of affected neonates to allow timely institution of therapy, (3) preconditioning therapy (a therapeutic that reduces the brain vulnerability) before hypoxic-ischemic encephalopathy, and (4) prompt institution of postinsult therapies to ameliorate the evolving injury. Recent clinical trials have demonstrated the significant benefit for hypothermic therapy in the postnatal period; furthermore, there is accumulating preclinical evidence that adjunctive therapies can enhance hypothermic neuroprotection. Advances in the understanding of preconditioning may lead to the administration of neuroprotective agents earlier during childbirth. Although most of these neuroprotective strategies have not yet entered clinical practice, there is a significant hope that further developments will enhance hypothermic neuroprotection.

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