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Glycerol-3-Phosphate Acyltransferase-1 Gene Ablation Results in Altered Thymocyte Lipid Content and Reduces Thymic T Cell Production in Mice

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Lipids

Abstract

Glycerol 3-phosphate acyltransferase-1 (GPAT-1) catalyzes the initial and rate-limiting step in de novo glycerophospholipid and triacylglycerol (TAG) biosynthesis. We have previously shown that peripheral T cell proliferation and cytokine production is altered in GPAT-1 gene-ablated (KO) mice. This finding is important in light of the reduction in GPAT-1 activity associated with aged T cells. To determine if the mechanism for altered peripheral T cell function is linked to altered T cell development, we assessed thymic function in 3, 6 and 16-week old GPAT-1 KO compared to wild type (WT) mice. At 16 weeks of age, there was a significant reduction in thymic T cell production in KO compared to WT mice but not at 6 weeks of age. The reduced thymic T cell production was associated with altered thymic development as confirmed by increased numbers of double-negative (DN) thymocytes and a significant reduction in the double positive (DP) thymocytes suggesting a developmental block at the DN stage. This change was accompanied by an increase in the single positive CD4 subset. These changes were associated with reduced glycerophospholipid mass while thymic cortex and medulla architecture was not altered by GPAT-1 KO. Taken together, these data suggest that GPAT-1 deletion is capable of reducing the number of new T cells produced via alterations in membrane receptor function rather than by causing deleterious changes within the thymic microenvironment explaining in part the observed alterations in peripheral T cell function.

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Abbreviations

Ptd2Gro:

Cardiolipin

CPT-1:

Carnitine Palmitoyl Transferase-1

AMPK:

5′Adenosine monophosphate-activated protein kinase

DN:

Double negative

DP:

Double positive

GPAT-1:

Glycerol-3-phosphate acyltransferase-1

NaHCO3 :

Sodium bicarbonate

NaN3 :

Sodium Azide

pAMPK:

Phospho-5′-adenosine monophosphate-activated protein kinase

PtdOH:

Phosphatidic acid

PBS:

Phosphate buffered saline

ChoGpl:

Choline glycerophospholipids

EtnGpl:

Ethanolamine glycerophospholipids

PtdIns:

Phosphatidylinositol

PtdSer:

Phosphatidylserine

CerPCho:

Sphingomyelin

SP:

Single positive

References

  1. Mathis D, Shoelson SE (2011) Immunometabolism: an emerging frontier. Nat Rev Immunol 11:81

    Article  PubMed  CAS  Google Scholar 

  2. Powell JD, Delgoffe GM (2010) The mammalian target of rapamycin: linking T cell differentiation, function, and metabolism. Immunity 33:301–311

    Article  PubMed  CAS  Google Scholar 

  3. Pearce EL, Walsh MC, Cejas PJ, Harms GM, Shen H, Wang L-S, Jones RG, Choi Y (2009) Enhancing CD8 T-cell memory by modulating fatty acid metabolism. Nature 460:103–107

    Article  PubMed  CAS  Google Scholar 

  4. Wendel AA, Lewin TM, Coleman RA (2009) Glycerol-3-phosphate acyltransferases: rate limiting enzymes of triacylglycerol biosynthesis. Biochim Biophys Acta 1791:501–506

    Article  PubMed  CAS  Google Scholar 

  5. Takeuchi K, Reue K (2009) Biochemistry, physiology, and genetics of GPAT, AGPAT, and lipin enzymes in triglyceride synthesis. Am J Physiol: Endocrin 296:E1195–E1209

    Article  CAS  Google Scholar 

  6. Gonzalez-Baro MR, Lewin TM, Coleman RA (2007) Regulation of triglyceride metabolism II. function of mitochondrial GPAT1 in the regulation of triacylglycerol biosynthesis and insulin action. Am J Physiol Gastrointest Liver Physiol 292:G1195–G1199

    Article  PubMed  CAS  Google Scholar 

  7. Collison LW, Murphy EJ, Jolly CA (2008) Glycerol-3-phosphate acyltransferase-1 regulates murine T-lymphocyte proliferation and cytokine production. Am J Physiol: Cell Physiol 295:C1543–C1549

    Article  CAS  Google Scholar 

  8. Stapleton CM, Mashek DG, Wang S, Nagle CA, Cline GW, Thuillier P, Leesnitzer LM, Li LO, Stimmel JB, Shulman GI, Coleman RA (2011) Lysophosphatidic acid activates peroxisome proliferator activated receptor-γ in CHO cells that over-express glycerol 3-phosphate acyltransferase-1. PLoS ONE 6:e18932

    Article  PubMed  CAS  Google Scholar 

  9. Zhang C, Wendel AA, Keogh MR, Harris TE, Chen J, Coleman RA (2012) Glycerolipid signals alter mTOR complex 2 (mTORC2) to diminish insulin signaling. Proc Natl Acad Sci 109:1667–1672

    Article  PubMed  CAS  Google Scholar 

  10. Collison LW, Jolly CA (2006) Phosphorylation regulates mitochondrial glycerol-3-phosphate-1 acyltransferase activity in T-lymphocytes. Biochim Biophys Acta 1761:129–139

    Article  PubMed  CAS  Google Scholar 

  11. Karlsson EA, Wang S, Shi Q, Coleman RA, Beck MA (2009) Glycerol-3-phosphate acyltransferase 1 is essential for the immune response to infection with Coxsackie virus B3 in Mice. J Nutr 139(4):779–783

    Article  PubMed  CAS  Google Scholar 

  12. Collison LW, Kannan L, Onorato TM, Knudsen J, Haldar D, Jolly CA (2005) Aging reduces glycerol-3-phosphate acyltransferase activity in activated rat splenic T-lymphocytes. Biochim Biophys Acta 1687:164–172

    Article  PubMed  CAS  Google Scholar 

  13. Lim BO, Jolly CA, Zaman K, Fernandes G (2000) Dietary (n-6) and (n-3) fatty acids and energy restriction modulate mesenteric lymph node lymphocyte function in autoimmune-prone (NZB × NZW) F1 mice. J Nutr 130:1657–1664

    PubMed  CAS  Google Scholar 

  14. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695

    Article  PubMed  CAS  Google Scholar 

  15. Xu Z, George C, Jolly CA (2004) CD28 activation does not down-regulate Cbl-b expression in aged rat T-lymphocytes. Mech Ag Develop 125:595–602

    Article  CAS  Google Scholar 

  16. Klug DB, Carter C, Gimenez-Conti IB, Richie ER (2002) Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 169:2842–2845

    PubMed  CAS  Google Scholar 

  17. Yang H, Youm Y-H, Vandanmagsar B, Rood J, Kumar KG, Butler AA, Dixit VD (2009) Obesity accelerates thymic aging. Blood 114:3803–3812

    Article  PubMed  CAS  Google Scholar 

  18. Yang H, Youm Y-H, Dixit VD (2009) Inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution. J Immunol 183:3040–3052

    Article  PubMed  CAS  Google Scholar 

  19. Littman DR (1999) The regulation of CD4 and CD8 coreceptor gene expression during T cell development. Ann Rev Immunol 17:523–554

    Article  Google Scholar 

  20. Finlay D, Cantrell DA (2011) Metabolism, migration and memory in cytotoxic T cells. Nat Rev Immunol 11:109–117

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Nutritional Sciences, Dell Pediatric Research Institute – R1800, The University of Texas at Austin, 1400 Barbara Jordan Blvd., Austin, TX, 78723-3092, USA

    Apeksha A. Gulvady, Robert M. Cabrera & Christopher A. Jolly

  2. Department of Physiology and Pharmacology, The University of North Dakota, Grand Forks, ND, USA

    Eric J. Murphy

  3. Office of Cancer Centers, National Cancer Institute, 6116 Executive Blvd., Rockville, MD, 20852, USA

    Henry P. Ciolino

Authors
  1. Apeksha A. Gulvady
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  2. Eric J. Murphy
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  3. Henry P. Ciolino
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  4. Robert M. Cabrera
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  5. Christopher A. Jolly
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Corresponding author

Correspondence to Christopher A. Jolly.

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Gulvady, A.A., Murphy, E.J., Ciolino, H.P. et al. Glycerol-3-Phosphate Acyltransferase-1 Gene Ablation Results in Altered Thymocyte Lipid Content and Reduces Thymic T Cell Production in Mice. Lipids 48, 3–12 (2013). https://doi.org/10.1007/s11745-012-3741-7

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  • DOI: https://doi.org/10.1007/s11745-012-3741-7

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