Thomas N Seyfried

St. Jude Children's Research Hospital, Memphis, Tennessee, United States

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Publications (216)829.75 Total impact

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    Joshua J Meidenbauer · Purna Mukherjee · Thomas N Seyfried
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    ABSTRACT: Metabolic therapy using ketogenic diets (KD) is emerging as an alternative or complementary approach to the current standard of care for brain cancer management. This therapeutic strategy targets the aerobic fermentation of glucose (Warburg effect), which is the common metabolic malady of most cancers including brain tumors. The KD targets tumor energy metabolism by lowering blood glucose and elevating blood ketones (β-hydroxybutyrate). Brain tumor cells, unlike normal brain cells, cannot use ketone bodies effectively for energy when glucose becomes limiting. Although plasma levels of glucose and ketone bodies have been used separately to predict the therapeutic success of metabolic therapy, daily glucose levels can fluctuate widely in brain cancer patients. This can create difficulty in linking changes in blood glucose and ketones to efficacy of metabolic therapy. A program was developed (Glucose Ketone Index Calculator, GKIC) that tracks the ratio of blood glucose to ketones as a single value. We have termed this ratio the Glucose Ketone Index (GKI). The GKIC was used to compute the GKI for data published on blood glucose and ketone levels in humans and mice with brain tumors. The results showed a clear relationship between the GKI and therapeutic efficacy using ketogenic diets and calorie restriction. The GKIC is a simple tool that can help monitor the efficacy of metabolic therapy in preclinical animal models and in clinical trials for malignant brain cancer and possibly other cancers that express aerobic fermentation.
    Preview · Article · Dec 2015 · Nutrition & Metabolism
  • Nathan L Ta · Thomas N Seyfried
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    ABSTRACT: Glucose and glutamine are essential energy metabolites for brain tumor growth and survival under both normoxic and hypoxic conditions. Both metabolites can contribute their carbons to lipid biosynthesis. We used uniformly labeled [(14)C]-U-D-glucose and [(14)C]-U-L-glutamine to examine the profile of de novo lipid biosynthesis in the VM-M3 murine glioblastoma cells. The major lipids synthesized included phosphatidylcholine (PtdCho), phosphatidylethanolamine (EtnGpl), phosphatidylinositol (PtdIns), phosphatidylserine (PtdSer), sphingomyelin (CerPCho), bis(monoacylglycero)phosphate (BMP)/phosphatidic acid (PtdOH), cholesterol (C), cardiolipin (Ptd2Gro), and gangliosides. Endogenous lipid synthesis, using either glucose or glutamine, was greater in media without fetal bovine serum (FBS) than in media containing 10 % FBS under normoxia. De novo lipid synthesis was greater using glucose carbons than glutamine carbons under normoxia. The reverse was observed for most lipids under hypoxia suggesting an attenuation of glucose entering the TCA cycle. Lactate was produced largely from glucose carbons with minimal lactate derived from glutamine under either normoxia or hypoxia. Accumulation of triacylglycerols (TAG), containing mostly saturated and mono-unsaturated fatty acids, was observed under hypoxia using carbons from either glucose or glutamine. The data show that the incorporation of labeled glucose and glutamine into most synthesized lipids was dependent on the type of growth environment, and that the VM-M3 glioblastoma cells could acquire lipids, especially cholesterol, from the external environment for growth and proliferation.
    No preview · Article · Nov 2015 · Lipids
  • Zeynep Akgoc · Sonia Iosim · Thomas N Seyfried
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    ABSTRACT: Bis(monoacylglycero)phosphate (BMP) is a structural isomer of phosphatidylglycerol (PtdGro) with an unusual sn-1:sn-1' fatty acyl configuration and is found almost exclusively in late endosomes/lysosomes. BMP comprises only about 1-2 % of the total phospholipids in most mammalian cells, but accumulates in tissues of humans and animals with lysosomal storage disorders including the gangliosidoses. Total BMP content was significantly greater in cells of macrophage/microglial origin than in cells of macroglial origin. BMP composition was similar in tumorigenic/metastatic macrophages and non-tumorigenic macrophages/microglia. Finally, BMP fatty acid composition differed between cells grown in culture and obtained in vivo suggesting an influence from growth environment.
    No preview · Article · Jul 2015 · Lipids
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    A M Poff · N Ward · T N Seyfried · P Arnold · D P D 'agostino
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    ABSTRACT: The Warburg effect and tumor hypoxia underlie a unique cancer metabolic phenotype characterized by glucose dependency and aerobic fermentation. We previously showed that two non-toxic metabolic therapies – the ketogenic diet with concurrent hyperbaric oxygen (KD+ HBOT) and dietary ketone supplementation – could increase survival time in the VM-M3 mouse model of metastatic cancer. We hypothesized that combining these therapies could provide an even greater therapeutic benefit in this model. Mice receiving the combination therapy demonstrated a marked reduction in tumor growth rate and metastatic spread, and lived twice as long as control animals. To further understand the effects of these metabolic therapies , we characterized the effects of high glucose (control), low glucose (LG), ketone supple-mentation (βHB), hyperbaric oxygen (HBOT), or combination therapy (LG+βHB+HBOT) on VM-M3 cells. Individually and combined, these metabolic therapies significantly decreased VM-M3 cell proliferation and viability. HBOT, alone or in combination with LG and βHB, increased ROS production in VM-M3 cells. This study strongly supports further investigation into this metabolic therapy as a potential non-toxic treatment for late-stage metastatic cancers.
    Full-text · Article · Jun 2015 · PLoS ONE
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    ABSTRACT: Sandhoff disease (SD) is an autosomal recessive neurodegenerative disease caused by a mutation in the gene for the β-subunit of β-N-acetylhexosaminidase (Hex), resulting in the inability to catabolize ganglioside GM2 within the lysosomes. SD presents with an accumulation of GM2 and its asialo derivative GA2, primarily in the central nervous system. Myelin-enriched glycolipids, cerebrosides and sulfatides, are also decreased in SD corresponding with dysmyelination. At present, no treatment exists for SD. Previous studies have shown the therapeutic benefit of adeno-associated virus (AAV) vector-mediated gene therapy in the treatment of SD in murine and feline models. In this study, we treated presymptomatic SD cats with AAVrh8 vectors expressing feline Hex in the thalamus combined with intracerebroventricular (Thal/ICV) injections. Treated animals showed clearly improved neurologic function and quality of life, manifested in part by prevention or attenuation of whole-body tremors characteristic of untreated animals. Hex activity was significantly elevated, whereas storage of GM2 and GA2 was significantly decreased in tissue samples taken from the cortex, cerebellum, thalamus, and cervical spinal cord. Treatment also increased levels of myelin-enriched cerebrosides and sulfatides in the cortex and thalamus. This study demonstrates the therapeutic potential of AAV for feline SD and suggests a similar potential for human SD patients. © The Author(s) 2015.
    Preview · Article · Apr 2015 · ASN Neuro
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    A M Poff · C Ari · P Arnold · T N Seyfried · D P D'Agostino

    Full-text · Dataset · Mar 2015
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    ABSTRACT: Bis(monoacylglycero)phosphate (BMP) is a negatively charged glycerophospholipid with an unusual structural configuration. BMP is primarily enriched in endosomal/lysosomal membranes. BMP is thought to play a role in glycosphingolipid degradation and cholesterol transport. Elevated BMP levels have been found in many lysosomal storage diseases suggesting an association with lysosomal storage material. The gangliosidoses are a group of neurodegenerative lysosomal storage diseases involving the accumulation of either GM1 or GM2 gangliosides resulting from inherited deficiencies in β-galactosidase or β-hexosaminidase, respectively. Little information is available on BMP levels in gangliosidosis brain tissue. Our results showed that the content of BMP in brain was significantly greater in humans and in animals (mice, cats, American black bears) with either GM1 or GM2 ganglioside storage diseases, than in brains of normal subjects. The storage of BMP and ganglioside GM2 in brain were reduced similarly following AAV-mediated gene therapy in Sandhoff disease mice. We also found that C22:6 , C18:0 and C18:1 were the predominant BMP fatty acid species in gangliosidosis brains. The results show that BMP accumulates as a secondary storage material in the brain of a broad range of mammals with gangliosidoses. Copyright © 2015, The American Society for Biochemistry and Molecular Biology.
    No preview · Article · Mar 2015 · The Journal of Lipid Research
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    ABSTRACT: GM1-gangliosidosis is a glycosphingolipid lysosomal storage disease involving accumulation of GM1 and its asialo form (GA1) primarily in the brain. Thin-layer chromatography and X-ray diffraction were used to analyze the lipid content/composition and the myelin structure of the optic and sciatic nerves from 7- and 10-month old β-galactosidase (β-gal) +/? and β-gal -/- mice, a model of GM1gangliosidosis. Optic nerve weight was lower in the β-gal -/- mice than in unaffected β-gal +/? mice, but no difference was seen in sciatic nerve weight. The levels of GM1 and GA1 were significantly increased in both the optic nerve and sciatic nerve of the β-gal -/- mice. The content of myelin-enriched cerebrosides, sulfatides, and plasmalogen ethanolamines was significantly lower in optic nerve of β-gal -/- mice than in β-gal +/? mice; however, cholesteryl esters were enriched in the β-gal -/- mice. No major abnormalities in these lipids were detected in the sciatic nerve of the β-gal -/- mice. The abnormalities in GM1 and myelin lipids in optic nerve of β-gal -/- mice correlated with a reduction in the relative amount of myelin and periodicity in fresh nerve. By contrast, the relative amount of myelin and periodicity in the sciatic nerves from control and β-gal -/- mice were indistinguishable, suggesting minimal pathological involvement in sciatic nerve. Our results indicate that the greater neurochemical pathology observed in the optic nerve than in the sciatic nerve of β-gal -/- mice is likely due to the greater glycolipid storage in optic nerve. © The Author(s) 2015.
    Full-text · Article · Feb 2015 · ASN Neuro
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    ABSTRACT: Sandhoff disease (SD) is caused by deficiency of N-acetyl-β-hexosaminidase (Hex) resulting in pathological accumulation of GM2 ganglioside in lysosomes of the central nervous system (CNS) and progressive neurodegeneration. Currently, there is no treatment for SD, which often results in death by the age of five years. Adeno-associated virus (AAV) gene therapy achieved global CNS Hex restoration and widespread normalization of storage in the SD mouse model. Using a similar treatment approach, we sought to translate the outcome in mice to the feline SD model as an important step toward human clinical trials. Sixteen weeks after four intracranial injections of AAVrh8 vectors, Hex activity was restored to above normal levels throughout the entire CNS and in cerebrospinal fluid, despite a humoral immune response to the vector. In accordance with significant normalization of a secondary lysosomal biomarker, ganglioside storage was substantially improved, but not completely cleared. At the study endpoint, 5-month-old AAV-treated SD cats had preserved neurological function and gait compared with untreated animals (humane endpoint, 4.4±0.6 months) demonstrating clinical benefit from AAV treatment. Translation of widespread biochemical disease correction from the mouse to the feline SD model provides optimism for treatment of the larger human CNS with minimal modification of approach.Gene Therapy advance online publication, 4 December 2014; doi:10.1038/gt.2014.108.
    No preview · Article · Dec 2014 · Gene Therapy
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    A M Poff · C Ari · P Arnold · T N Seyfried · D P D'Agostino
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    ABSTRACT: Cancer cells express an abnormal metabolism characterized by increased glucose consumption due to genetic mutations and mitochondrial dysfunction. Previous studies indicate that unlike healthy tissues, cancer cells are unable to effectively utilize ketone bodies for energy. Furthermore, ketones inhibit the proliferation and viability of cultured tumor cells. As the Warburg effect is especially prominent in metastatic cells, we hypothesized that dietary ketone supplementation would inhibit metastatic cancer progression in vivo. Proliferation and viability were measured in the highly metastatic VM-M3 cells cultured in the presence and absence of β-hydroxybutyrate (βHB). Adult male inbred VM mice were implanted subcutaneously with firefly-luciferase tagged syngeneic VM-M3 cells. Mice were fed a standard diet supplemented with either 1,3-butanediol (BD) or a ketone ester (KE), which are metabolized to the ketone bodies β-hydroxybutyrate (βHB) and acetoacetate (AcAC). Tumor growth was monitored by in vivo bioluminescent imaging. Survival time, tumor growth rate, blood glucose, blood βHB, and body weight were measured throughout the survival study. Ketone supplementation decreased proliferation and viability of the VM-M3 cells grown in vitro, even in the presence of high glucose. Dietary ketone supplementation with BD and KE prolonged survival in VM-M3 mice with systemic metastatic cancer by 51% and 69%, respectively (p<0.05). Ketone administration elicited anti-cancer effects in vitro and in vivo independent of glucose levels or calorie restriction. The use of supplemental ketone precursors as a cancer treatment should be further investigated in animal models to determine potential for future clinical use. © 2014 Wiley Periodicals, Inc.
    Full-text · Article · Oct 2014 · International Journal of Cancer
  • Roberto Flores · Ashley K. Brown · Zeynep Akgoc · Thomas N. Seyfried

    No preview · Article · Oct 2014 · Cancer Research
  • Zeynep Akgoc · Laura M. Shelton · David Ryan · Xijun Zhu · Thomas N. Seyfried

    No preview · Article · Oct 2014 · Cancer Research
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    ABSTRACT: Although the biochemical and genetic basis for the GM1 and GM2 gangliosidoses has been known for decades, effective therapies for these diseases remain in early stages of development. The difficulty with many therapeutic strategies for treating the gangliosidoses comes largely from their inability to remove stored ganglioside once it accumulates in central nervous system (CNS) neurons and glia. This chapter highlights advances made using substrate reduction therapy and gene therapy in reducing CNS ganglioside storage. Information obtained from mouse and feline models provides insight on therapeutic strategies that could be effective in human clinical trials. In addition, information is presented showing how a calorie-restricted diet might facilitate therapeutic drug delivery to the CNS. The development of multiple new therapeutic approaches offers hope that longer-term management of these diseases can be achieved. It is also clear that multiple therapeutic strategies will likely be needed to provide the most complete management.
    No preview · Article · Aug 2014 · Advances in neurobiology
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    ABSTRACT: Little progress has been made in the long-term management of glioblastoma multiforme (GBM), considered among the most lethal of brain cancers. Cytotoxic chemotherapy, steroids, and high-dose radiation are generally used as the standard of care for GBM. These procedures can create a tumor microenvironment rich in glucose and glutamine. Glucose and glutamine are suggested to facilitate tumor progression. Recent evidence suggests that many GBMs are infected with cytomegalovirus, which could further enhance glucose and glutamine metabolism in the tumor cells. Emerging evidence also suggests that neoplastic macrophages/microglia, arising through possible fusion hybridization, can comprise an invasive cell subpopulation within GBM. Glucose and glutamine are major fuels for myeloid cells, as well as for the more rapidly proliferating cancer stem cells. Therapies that increase inflammation and energy metabolites in the GBM microenvironment can enhance tumor progression. In contrast to current GBM therapies, metabolic therapy is designed to target the metabolic malady common to all tumor cells (aerobic fermentation), while enhancing the health and vitality of normal brain cells and the entire body. The calorie restricted ketogenic diet (KD-R) is an anti-angiogenic, anti-inflammatory and pro-apoptotic metabolic therapy that also reduces fermentable fuels in the tumor microenvironment. Metabolic therapy, as an alternative to the standard of care, has the potential to improve outcome for patients with GBM and other malignant brain cancers.
    No preview · Article · Jul 2014 · Cancer Letters
  • Thomas N Seyfried

    No preview · Article · Jul 2014 · The Journal of Lipid Research
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    ABSTRACT: The ketogenic diet (KD) is known to be anticonvulsant and anti-epileptogenic. While the mechanism behind this therapeutic benefit is unclear, a reduction of circulating glucose levels through calorie restriction (CR) has been implicated. Foods or drinks that elevate blood glucose are known to compromise the therapeutic benefit of the KD in some children with epilepsy. We therefore evaluated the effect of a calorie restricted KD (KD-R) with supplementation of glucose in the drinking water of EL mice, a natural model of idiopathic generalized epilepsy, prior to seizure testing to assess the effect of glucose on seizure generation. Mice were fed either a standard diet or the KD unrestricted (SD-UR and KD-UR, respectively), or the KD restricted (KD-R). d-Glucose (25mM) was supplemented in the drinking water of KD-R fed mice for 0.5h or for 2.5h prior to seizure testing. Each restricted mouse served as its own body weight control to achieve a 15-18% body weight reduction. Seizure susceptibility, body weights, and plasma glucose and β-hydroxybutyrate levels were measured over a nine-week treatment period. Body weights and glucose levels remained high over the testing period in both the SD-UR and the KD-UR groups, but were significantly reduced in all R-fed groups. A significant increase in β-hydroxybutyrate levels was observed in all KD groups. Seizure susceptibility remained highest in the SD-UR group, was slightly reduced in the KD-UR group, and was significantly reduced after three weeks in all R-fed groups. Supplementation of glucose prior to seizure testing resulted in a decrease of seizure threshold for R-fed mice, but did not alter bodyweight or circulating glucose levels. The KD has both an anticonvulsant and antiepileptogenic effect in EL mice. Here we confirm that CR enhances the anticonvulsant action of the KD in EL mice. Additionally, we show for the first time that supplementation of glucose decreases the anticonvulsant action of the KD, which further supports the hypothesis that CR works through transitioning metabolism from glucose to ketone utilization for energy.
    Full-text · Article · Jun 2014 · Epilepsy Research
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    [Show abstract] [Hide abstract]
    ABSTRACT: The ketogenic diet (KD) is known to be anticonvulsant and anti-epileptogenic. While the mechanism behind this therapeutic benefit is unclear, a reduction of circulating glucose levels through calorie restriction (CR) has been implicated. Foods or drinks that elevate blood glucose are known to compromise the therapeutic benefit of the KD in some children with epilepsy. We therefore evaluated the effect of a calorie restricted KD (KD-R) with supplementation of glucose in the drinking water of EL mice, a natural model of idiopathic generalized epilepsy, prior to seizure testing to assess the effect of glucose on seizure generation. Mice were fed either a standard diet or the KD unrestricted (SD-UR and KD-UR, respectively), or the KD restricted (KD-R). D-Glucose (25 mM) was supplemented in the drinking water of KD-R fed mice for 0.5 hours or for 2.5 hours prior to seizure testing. Each restricted mouse served as its own body weight control to achieve a 15-18% body weight reduction. Seizure susceptibility, body weights, and plasma glucose and β-hydroxybutyrate levels were measured over a nine-week treatment period. Body weights and glucose levels remained high over the testing period in both the SD-UR and the KD-UR groups, but were significantly reduced in all R-fed groups. A significant increase in β-hydroxybutyrate levels was observed in all KD groups. Seizure susceptibility remained highest in the SD-UR group, was slightly reduced in the KD-UR group, and was significantly reduced after three weeks in all R-fed groups. Supplementation of glucose prior to seizure testing resulted in a decrease of seizure threshold for R-fed mice, but did not alter bodyweight or circulating glucose levels. The KD has both an anticonvulsant and antiepileptogenic effect in EL mice. Here we confirm that CR enhances the anticonvulsant action of the KD in EL mice. Additionally, we show for the first time that supplementation of glucose decreases the anticonvulsant action of the KD, which further supports the hypothesis that CR works through transitioning metabolism from glucose to ketone utilization for energy.
    Full-text · Article · Jun 2014
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    Joshua J. Meidenbauer · Nathan Ta · Thomas N. Seyfried
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    ABSTRACT: Background Diet therapies including calorie restriction, ketogenic diets, and fish-oil supplementation have been used to improve health and to treat a variety of neurological and non-neurological diseases. Methods We investigated the effects of three diets on circulating plasma metabolites (glucose and β-hydroxybutyrate), hormones (insulin and adiponectin), and lipids over a 32-day period in C57BL/6J mice. The diets evaluated included a standard rodent diet (SD), a ketogenic diet (KD), and a standard rodent diet supplemented with fish-oil (FO). Each diet was administered in either unrestricted (UR) or restricted (R) amounts to reduce body weight by 20%. Results The KD-UR increased body weight and glucose levels and promoted a hyperlipidemic profile, whereas the FO-UR decreased body weight and glucose levels and promoted a normolipidemic profile, compared to the SD-UR. When administered in restricted amounts, all three diets produced a similar plasma metabolite profile, which included decreased glucose levels and a normolipidemic profile. Linear regression analysis showed that circulating glucose most strongly predicted body weight and triglyceride levels, whereas calorie intake moderately predicted glucose levels and strongly predicted ketone body levels. Conclusions These results suggest that biomarkers of health can be improved when diets are consumed in restricted amounts, regardless of macronutrient composition.
    Full-text · Article · May 2014 · Nutrition & Metabolism
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    ABSTRACT: GM1-gangliosidosis is a rare progressive neurodegenerative disorder due to an autosomal recessively inherited deficiency of lysosomal β-galactosidase. We have identified seven American Black Bears (Ursus americanus) found in the Northeast United States suffering from GM1-gangliosidosis. This report describes the clinical features, brain MRI, morphologic, biochemical and molecular genetic findings in the affected bears. Brain lipids were compared with those in the brain of the GM1-mouse. The bears presented at ages 10 – 14 months in poor clinical condition, lethargic, tremulous and ataxic. They continued to decline and were humanely euthanized. The T2-weighted MR images of the brain of one bear disclosed white matter hyperintensity. Morphological studies of brain from five of the bears revealed enlarged neurons with foamy cytoplasm containing granules. Axonal spheroids were present in white matter. Electron microscopic examination revealed lamellated membrane structures within neurons. Cytoplasmic vacuoles were found in the liver, kidneys and chondrocytes and foamy macrophages within the lungs. Acid β-galactosidase activity in cultured skin fibroblasts was only 1–2 percent of control values. In brain, ganglioside-bound sialic acid was increased more than 2-fold with GM1-ganglioside predominating. GA1 content was also increased whereas cerebrosides and sulfatides were markedly decreased. The distribution of gangliosides was similar to that in GM1-mouse brain, but the loss of myelin lipids was greater in the brain of the affected bear than in the brain of the GM1 mouse. Isolated full-length cDNA of the black bear GLB1 gene revealed 86% homology to its human counterpart in nucleotide sequence and 82% in amino acid sequence. GLB1 cDNA from liver tissue of an affected bear contained a homozygous recessive T1042 to C transition inducing a Tyr348 to His mutation (Y348H) within a highly conserved region of the GLB1 gene. The coincidence of several Black Bears with GM1-gangliosidosis in the same geographic area suggests increased frequency of a founder mutation in this animal population.
    No preview · Article · Apr 2014 · Molecular Genetics and Metabolism
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    ABSTRACT: Bacterially derived lipopolysaccharide (LPS) stimulates naive B lymphocytes to differentiate into immunoglobulin (Ig)-secreting plasma cells. Differentiation of B lymphocytes is characterized by a proliferative phase followed by expansion of the intracellular membrane secretory network to support Ig production. A key question in lymphocyte biology is how naive B cells reprogram metabolism to support de novo lipogenesis necessary for proliferation and expansion of the endomembrane network in response to LPS. We report that extracellularly acquired glucose is metabolized, in part, to support de novo lipogenesis in response to LPS stimulation of splenic B lymphocytes. LPS stimulation leads to increased levels of endogenous ATP-citrate lyase (ACLY), and this is accompanied by increased ACLY enzymatic activity. ACLY produces cytosolic acetyl-CoA from mitochondrially derived citrate. Inhibition of ACLY activity in LPS-stimulated B cells with the selective inhibitor 2-hydroxy-N-arylbenzenesulfonamide (compound-9; C-9) blocks glucose incorporation into de novo lipid biosynthesis, including cholesterol, free fatty acids, and neutral and acidic phospholipids. Moreover, inhibition of ACLY activity in splenic B cells results in inhibition of proliferation and defective endomembrane expansion and reduced expression of CD138 and Blimp-1, markers for plasma-like B cell differentiation. ACLY activity is also required for LPS-induced IgM production in CH12 B lymphoma cells. These data demonstrate that ACLY mediates glucose-dependent de novo lipogenesis in response to LPS signaling and identify a role for ACLY in several phenotypic changes that define plasma cell differentiation.
    Full-text · Article · Jan 2014 · Journal of Biological Chemistry

Publication Stats

6k Citations
829.75 Total Impact Points

Institutions

  • 2015
    • St. Jude Children's Research Hospital
      • Department of Genetics
      Memphis, Tennessee, United States
    • University of Massachusetts Medical School
      • Gene Therapy Center
      Worcester, Massachusetts, United States
  • 1989-2015
    • Boston College, USA
      • Biology Department
      Boston, Massachusetts, United States
  • 1987-2015
    • Chestnut Hill College
      Boston, Massachusetts, United States
  • 2013
    • University of South Florida
      • Division of Molecular Pharmacology & Physiology
      Tampa, Florida, United States
  • 2010
    • University of California, San Francisco
      • Division of Hematology and Medical Oncology
      San Francisco, California, United States
  • 2007
    • Washington University in St. Louis
      San Luis, Missouri, United States
  • 2006
    • Harvard Medical School
      • Department of Neurology
      Boston, Massachusetts, United States
  • 2004
    • University of Oxford
      • Department of Biochemistry
      Oxford, England, United Kingdom
  • 2003
    • Massachusetts Institute of Technology
      • Department of Biology
      Cambridge, Massachusetts, United States
  • 1999
    • Geisel School of Medicine at Dartmouth
      Hanover, New Hampshire, United States
  • 1994
    • Boston Medical Center
      Boston, Massachusetts, United States
  • 1978-1986
    • Yale-New Haven Hospital
      New Haven, Connecticut, United States
  • 1977-1984
    • Yale University
      • Department of Neurology
      New Haven, Connecticut, United States
  • 1976
    • University of Illinois, Urbana-Champaign
      Urbana, Illinois, United States