Skip to main content
Log in

Tissue-dependent alterations in lipid mass in mice lacking glycerol kinase

  • Articles
  • Published:
Lipids

Abstract

Glycerol kinase (ATP:glycerol-3-phosphotransferase, EC 2.7.1.30, glycerokinase) (Gyk) has a central role in plasma glycerol extraction and utilization by tissues for lipid biosynthesis. Gyk deficiency causes various phenotypic changes ranging from asymptomatic hyperglycerolemia to a severe metabolic disorder with growth and psychomotor retardation. To better understand the potential role of Gyk in tissue lipid metabolism, we determined phospholipid (PL), cholesterol (Chol), and triacylglycerol (TG) mass in a number of tissues from mice lacking Gyk. We report a tissue-dependent response to Gyk gene deletion. Tissues with elevated total PL mass (brain, kidney, muscle) were characterized by the increased mass of ethanolamine glycerophospholipids (EtnGpl), choline glycerophospholipids, and phosphatidylserine (PtdSer). In heart, lipid changes were characterized by a reduction in total PL, including decreased EtnGpl, phosphatidylinositol, and PtdSer mass and decreased TG and FFA mass. In parallel with tissue PL alterations, tissue Chol was also changed, maintaining a normal Chol/PL ratio. Under conditions of Gyk deficiency, we speculate that glycerol-3-phosphate and lipid production is maintained via alternative biosynthesis, including glycolysis, glyceroneogenesis, or by direct acylation of glycerol in brain, muscle, kidney, and liver, but not in heart.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

Abbreviations

Chol:

cholesterol

CerPCho:

sphingomyelin

ChoGpl:

choline glycerophospholipids

Gyk:

glycerol kinase

Gro-3-P:

glycerol-3-phosphate

EtnGpl:

ethanolamine glycerophospholipids

PL:

phospholipids

PtdSer:

phosphatidylserine

PtdIns:

phosphatidylinositol

TG:

triacylglycerol.

References

  1. Reshef, L., Olswang, Y., Cassuto, H., Blum, B., Croniger, C.M., Kalhan, S.C., Tilghman, S.M., and Hanson, R.W. (2003) Glyceroneogenesis and the Triglyceride/Fatty Acid Cycle, J. Biol. Chem. 278, 30413–30416.

    Article  PubMed  CAS  Google Scholar 

  2. Stroud, R.M., Savage, D., Miercke, L.J.W., Lee, J.K., Khademi, S., and Harries, W. (2003) Selectivity and Conductance Among the Glycerol and Water Conducting Aquaporine Family of Channels, FEBS Lett. 555, 79–84.

    Article  PubMed  CAS  Google Scholar 

  3. Bortz, W.M., Paul, P., Haff, A.C., and Holmes, W.L. (1972) Glycerol Turnover and Oxidation in Man, J. Clin. Invest. 51, 1537–1546.

    Article  PubMed  CAS  Google Scholar 

  4. Baba, H., Zhang, X.J., and Wolfe, R.R. (1995) Glycerol Gluconeogenesis in Fasting Humans, Nutrition 11, 149–153.

    PubMed  CAS  Google Scholar 

  5. Agteresch, H.J., Leij-Halfwerk, S., Van Den Berg, J.W., Hordijk-Luijk, C.H., Wilson, J.H., and Dagnelie, P.C. (2000) Effects of ATP Infusion on Glucose Turnover and Gluconeogenesis in Patients with Advanced Non-small-cell Lung Cancer, Clin. Sci. (London) 98, 689–695.

    CAS  Google Scholar 

  6. Previs, S.F., Martin, S.K., Hazey, J.W., Soloviev, M.V., Keating, A.P., Lucas, D., David, F., Koshy, J., Kirschenbaum, D.W., Tserng, K.Y., and Brunengraber, H. (1996) Contributions of Liver and Kidneys to Glycerol Production and Utilization in the Dog, Am. J. Physiol. 271, E1118-E1124.

    PubMed  CAS  Google Scholar 

  7. Guo, Z., and Jensen, M.D. (1999) Blood Glycerol Is an Important Precursor for Intramuscular Triacylglycerol Synthesis, J. Biol. Chem. 274, 23702–23706.

    Article  PubMed  CAS  Google Scholar 

  8. Nguyen, N.H., Brathe, A., and Hassel, B. (2003) Neuronal Uptake and Metabolism of Glycerol and the Neuronal Expression of Mitochondrial Glycerol-3-phosphate Dehydrogenase, J. Neurochem. 85, 831–842.

    Article  PubMed  CAS  Google Scholar 

  9. Pascual de Bazan, H.E., and Bazan, N.G. (1976) Phospholipid Composition and [14C]Glycerol Incorporation into Glycerolipids of Toad Retina and Brain, J. Neurochem. 27, 1051–1057.

    Article  PubMed  CAS  Google Scholar 

  10. Robinson, J., and Newsholme, E.A. (1967) Glycerol Kinase Activities in Rat Heart and Adipose Tissue, Biochem. J. 104, 2C-4C.

    PubMed  CAS  Google Scholar 

  11. Wolfe, R.R., Klein, S., Carraro, F., and Weber, J.M. (1990) Role of Triglyceride-Fatty Acid Cycle in Controlling Fat Metabolism in Humans During and After Exercise, Am. J. Physiol. 258, E382-E389.

    PubMed  CAS  Google Scholar 

  12. Carmaniu, S., and Herrera, E. (1980) Comparative Utilization in vivo of [U-14C]Glycerol, [2-3H]Glycerol, [U-14C]Glucose and [1-14C]Palmitate in the Rat, Arch. Int. Physiol. Biochim. 88, 255–263.

    PubMed  CAS  Google Scholar 

  13. Glaumann, H., Bergstrand, A., and Ericsson, J.L. (1975) Studies on the Synthesis and Intracellular Transport of Lipoprotein Particles in Rat Liver, J. Cell Biol. 64, 356–377.

    Article  PubMed  CAS  Google Scholar 

  14. Abdel-Latif, A.A., and Smith, J.P. (1970) In vivo Incorporation of Choline, Glycerol and Orthophosphate into Lecithin and Other Phospholipids of Subcellular Fractions of Rat Cerebrum, Biochim. Biophys. Acta 218 134–140.

    PubMed  CAS  Google Scholar 

  15. Lapetina, E.G., Rodriguez de Lores Arnaiz, G., and De Robertis, E. (1969) Turnover Rates for Glycerol, Acetate and Orthophosphate in Phospholipids of the Rat Cerebral Cortex, Biochim. Biophys. Acta 176, 643–646.

    PubMed  CAS  Google Scholar 

  16. Peroni, O., Large, V., Odeon, M., and Beylot, M. (1996) Measuring Glycerol Turnover, Gluconeogenesis from Glycerol, and Total Gluconeogenesis with [2–13C] Glycerol: Role of the Infusion-Sampling Mode, Metabolism 45 897–901.

    Article  PubMed  CAS  Google Scholar 

  17. Lumeng, L., Bremer, J., and Davis, E.J. (1976) Suppression of the Mitochondrial Oxidation of (−)-Palmitylcarnitine by the Malate-Aspartate and α-Glycerophosphate Shuttles, J. Biol. Chem. 251, 277–284.

    PubMed  CAS  Google Scholar 

  18. McCabe, E.R.B. (2001) Disorders of Glycerol Metabolism, in The Metabolic and Molecular Bases of Inherited Disease (Scriver, C., Beaudet, A.L., Sly, W.S., Valle, D., Childs, B., Kinzler, K.W., and Vogelstein, B., eds.), 8th edn., pp. 2217–2237, McGraw-Hill, New York.

    Google Scholar 

  19. Walker, A.P., Muscatelli, F., Stafford, A.N., Chelly, J., Dahl, N., Blomquist, H.K., Delanghe, J., Willems, P.J., Steinmann, B., and Monaco, A.P. (1996) Mutations and Phenotype in Isolated Glycerol Kinase Deficiency, Am. J. Hum. Genet. 58, 1205–1211.

    PubMed  CAS  Google Scholar 

  20. Dipple, K.M., Zhang, Y.-H., Huang, B.-L., McCabe, L.L., Dallongeville, J., Inokuchi, T., Kimura, M., Marx, H.J., Roederer, G.O., Shih, V., Yamaguchi, S., Yoshida, I., and McCabe, E.R.B., (2001) Glycerol Kinase Deficiency: Evidence for Complexity in a Single Gene Disorder, Hum. Genet. 109, 55–62.

    Article  PubMed  CAS  Google Scholar 

  21. Hellerud, C., Burlina, A., Gabelli, C., Ellis, J.R., Nyholm, P.G., and Lindstedt, S. (2003) Glycerol Metabolism and the Determination of Triglycerides—Clinical, Biochemical and Molecular Findings in Six Subjects, Clin. Chem. Lab. Med. 41, 46–55.

    Article  PubMed  CAS  Google Scholar 

  22. Hellerud, C., Adamowicz, M., Jurkiewicz, D., Taybert, J., Kubalska, J., Ciara, E., Popowska, E., Ellis, J.R., Lindstedt, S., and Pronicak, E. (2003) Clinical Heterogeneity and Molecular Findings in Five Polish Patients with Glycerol Kinase Deficiency: Investigation of Two Splice Site Mutations with Computerized Splice Junction Analysis and Xp21 Gene-Specific mRNA Analysis, Mol. Genet. Metab. 79, 149–159.

    Article  PubMed  CAS  Google Scholar 

  23. Mahbubul Huq, A.H., Lovell, R.S., Ou, C.-N., Beaudet, A.L., and Craigen, W.J. (1997) X-Linked Glycerol Kinase Deficiency in the Mouse Leads to Growth Retardation, Altered Fat Metabolism, Autonomous Glucocorticoid Secretion and Neonatal Death, Hum. Mol. Genet. 6, 1803–1809.

    Article  Google Scholar 

  24. Bartley, J.A., and Ward, R. (1985) Glycerol Kinase Deficiency Inhibits Glycerol Utilization in Phosphoglyceride and Triacylglycerol Biosynthesis, Pediatr. Res. 19, 313–314.

    PubMed  CAS  Google Scholar 

  25. Hara, A., and Radin, N.S. (1978) Lipid Extraction of Tissues with a Low-Toxicity Solvent, Anal. Biochem. 90, 420–426.

    Article  PubMed  CAS  Google Scholar 

  26. Saunders, R.D., and Horrocks, L.A. (1984) Simultaneous Extraction and Preparation for HPLC of Prostaglandins and Phospholipids, Anal. Biochem. 143, 71–75.

    Article  PubMed  CAS  Google Scholar 

  27. Dugan, L.L., Demediuk, P., Pendley, C.E., II, and Horrocks, L.A. (1986) Separation of Phospholipids by High Pressure Liquid Chromatography: All Major Classes Including Ethanolamine and Choline Plasmalogens, and Most Minor Classes, Including Lysophosphatidylethanolamine, J. Chromatogr. 378, 317–327.

    PubMed  CAS  Google Scholar 

  28. Murphy, E.J., Stephens, R., Jurkowitz-Alexander, M., and Horrocks, L.A. (1993) Acidic Hydrolysis of Plasmalogens Followed by High-Performance Liquid Chromatography, Lipids 28, 565–568.

    Article  PubMed  CAS  Google Scholar 

  29. Rouser, G., Siakotos, A., and Fleischer, S. (1969) Quantitative Analysis of Phospholipids by Thin Layer Chromatography and Phosphorus Analysis of Spots, Lipids 1, 85–86.

    Google Scholar 

  30. Murphy, E.J., Prows, D.R., Jefferson, J.R., and Schroeder, F. (1996) Liver Fatty Acid Binding Protein Expression in Transfected Fibroblasts Stimulates Fatty Acid Uptake and Metabolism, Biochim. Biophys. Acta 1301, 191–196.

    PubMed  Google Scholar 

  31. Murphy, E.J., Rosenberger, T.A., and Horrocks, L.A. (1996) Separation of Neutral Lipids by High Performance Liquid Chromatography: Quantification by Ultraviolet, Light Scattering and Fluorescent Detectors, J. Chromatogr. B 685, 9–14.

    CAS  Google Scholar 

  32. Akesson, B., Elovsson, J., and Arvidsson, G. (1970) Initial Incorporation into Rat Liver Glycerolipids of Intraportally Injected [3H]Glycerol, Biochim. Biophys. Acta 210, 15–27.

    PubMed  CAS  Google Scholar 

  33. Murphy, E.J., and Schroeder, F. (1997) Sterol Carrier Protein-2 Mediated Cholesterol Esterification in Transfected L-Cell Fibroblasts, Biochim. Biophys. Acta 1345, 283–292.

    PubMed  CAS  Google Scholar 

  34. Brockerhoff, H. (1975) Determination of the Positional Distribution of Fatty Acids in Glycerolipids. Methods Enzymol. 35, 315–325.

    PubMed  CAS  Google Scholar 

  35. Bradford, M. (1976) A Rapid and Sensitive Method for the Quantitation of Microgram Quantities of Protein Utilizing the Principle of Protein-Dye Binding, Anal. Biochem. 72, 248–254.

    Article  PubMed  CAS  Google Scholar 

  36. Brown, L.J., Kosa, R.A., Marshall, L., Kozak, L.P., and Mac-Donald, M.J. (2002) Lethal Hypoglycemic Ketosis and Glyceroluria in Mice Lacking Both the Mitochondrial and the Cytosolic Glycerol Phosphate Dehydrogenases, J. Biol. Chem. 277, 32899–32904.

    Article  PubMed  CAS  Google Scholar 

  37. Custo, G., Corazzi, L., Mastrofini, P., and Arienti, G. (1987) Glycerol Incorporation into Brain Lipids in Rat Pups Born to Ethanol-Intoxicated Dams, Neurochem. Res. 12, 469–473.

    Article  PubMed  CAS  Google Scholar 

  38. Tardi, P.G., Man, R.Y., and Choy, P.C. (1992) The Effect of Methyl-Lidocaine on the Biosynthesis of Phospholipids de novo in the Isolated Hamster Heart, Biochem. J. 285, 161–166.

    PubMed  CAS  Google Scholar 

  39. Athenstaedt, K., and Daum, G. (1999) Phosphatidic Acid, a Key Intermediate in Lipid Metabolism, Eur. J. Biochem. 266, 1–16.

    Article  PubMed  CAS  Google Scholar 

  40. Watford, M. (2000) Functional Glycerol Kinase Activity and the Possibility of a Major Role for Glyceroneogenesis in Mammalian Skeletal Muscle, Nutr. Rev. 58, 145–148.

    Article  PubMed  CAS  Google Scholar 

  41. Crabtree, B., and Newsholme, E.A. (1972) The Activities of Phosphorylase, Hexokinase, Phosphofructokinase, Lactate Dehydrogenase and the Glycerol 3-Phosphate Dehydrogenases in Muscles from Vertebrates and Invertebrates, Biochem. J. 126, 49–58.

    PubMed  CAS  Google Scholar 

  42. Duelli, R., Maurer, M.H., Staudt, R., Heiland, S., Duembgen, L., and Kuschinsky, W. (2000) Increased Cerebral Glucose Utilization and Decreased Glucose Transporter Glut1 During Chronic Hyperglycemia in Rat Brain, Brain Res. 858, 338–347.

    Article  PubMed  CAS  Google Scholar 

  43. Sokoloff, L., Reivich, M., Kennedy, C., Des Roisiers, M.H., Patlak, C.S., Pettigrew, K.D., Sakurada, O., and Shinohara, M. (1977) The [14C]Deoxyglucose Method for the Measurement of Local Cerebral Glucose Utilization: Theory, Procedure, and Normal Values in the Conscious and Anesthetized Albino Rat, J. Neurochem. 28, 897–916.

    Article  PubMed  CAS  Google Scholar 

  44. Garcia-Salguero, L., and Lupianez, J.A. (1989) Metabolic Adaptation of the Renal Carbohydrate Metabolism. II. Effects of a High Carbohydrate Diet on the Gluconeogenic and Glycolytic Fluxes in the Proximal and Distal Renal Tubules, Mol. Cell. Biochem. 85, 91–100.

    Article  PubMed  CAS  Google Scholar 

  45. Lee, D.P., Deonarine, A.S., Kienetz, M., Zhu, Q., Skrzypczak, M., Chan, M., and Choy, P.C. (2001) A Novel Pathway for Lipid Biosynthesis: The Direct Acylation of Glycerol, J. Lipid Res. 42, 1979–1986.

    PubMed  CAS  Google Scholar 

  46. Ma, T., Yang, B., and Verkman, A.S. (1997) Cloning of a Novel Water and Urea-Permeable Aquaporin from Mouse Expressed Strongly in Colon, Placenta, Liver, and Heart, Biochem. Biophys. Res. Commun. 240, 324–328.

    Article  PubMed  CAS  Google Scholar 

  47. DeGrella, R.F., and Light, R.J. (1980) Uptake and Metabolism of Fatty Acids by Dispersed Adult Rat Heart Myocytes. I. Kinetics of Homologous Fatty Acids, J. Biol. Chem. 255, 9731–9738.

    PubMed  CAS  Google Scholar 

  48. Klein, M.S., Goldstein, R.A., Welch, M.J., and Sobel, B.E. (1979) External Assessment of Myocardial Metabolism with [11C]Palmitate in Rabbit Hearts, Am. J. Physiol. 237, H51-H57.

    PubMed  CAS  Google Scholar 

  49. Tamboli, A., O'Looney, P., Vander Maten, M., and Vahouny, G.V. (1983) Comparative Metabolism of Free and Esterified Fatty Acids by the Perfused Rat Heart and Rat Cardiac Myocytes, Biochim. Biophys. Acta 750, 404–410.

    PubMed  CAS  Google Scholar 

  50. McMaster, C.R., and Bell, R.M. (1997) CDP-Choline: 1,2-Diacylglycerol Cholinephosphotransferase, Biochim. Biophys. Acta 1348, 100–110.

    PubMed  Google Scholar 

  51. McMaster, C.R., and Bell, R.M. (1997) CDP-Ethanolamine:1,2-Diacylglycerol Ethanolaminephosphotransferase, Biochim. Biophys. Acta 1348, 117–123.

    PubMed  CAS  Google Scholar 

  52. Araki, W., and Wurtman, R.J. (1998) How Is Membrane Phospholipid Biosynthesis Controlled in Neural Tissues? J. Neurosci. Res. 51, 667–674.

    Article  PubMed  CAS  Google Scholar 

  53. Heacock, A.M., and Agranoff, B.W. (1997) CDP-Diacylglycerol Synthase from Mammalian Tissues, Biochim. Biophys. Acta 1348, 166–172.

    PubMed  CAS  Google Scholar 

  54. Schroeder, F., Frolov, A.A., Murphy, E.J., Atshaves, B.P., Pu, L., Wood, W.G., Foxworth, W.B., and Kier, A.B. (1996) Recent Advances in Membrane Cholesterol Domain Dynamics and Intracellular Cholesterol Trafficking, Proc. Soc. Exp. Biol. Med. 213, 150–177.

    PubMed  CAS  Google Scholar 

  55. Wood, W.G., Schroeder, F., Avdulov, N.A., Chochina, S.V., and Igbauboa, U. (1999) Recent Advances in Brain Cholesterol Dynamics: Transport, Domains, and Alzheimer's Disease, Lipids 34, 225–234.

    Article  PubMed  CAS  Google Scholar 

  56. Petrovich, D.R., Finkelstein, S., Waring, A.J., and Farber, J.L. (1984) Liver Ischemia Increases the Molecular Order of Microsomal Membranes by Increasing the Cholesterol-to-Phospholipid Ratio, J. Biol. Chem. 259, 13217–13223.

    PubMed  CAS  Google Scholar 

  57. Murphy, E.J., Chapiro, M.B., Rapoport, S.I., and Shetty, H.U. (2000) Phospholipid Composition and Levels Are Altered in Down Syndrome Brain, Brain Res. 867, 9–18.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Eric J. Murphy.

About this article

Cite this article

Golovko, M.Y., Hovda, J.T., Cai, ZJ. et al. Tissue-dependent alterations in lipid mass in mice lacking glycerol kinase. Lipids 40, 287–293 (2005). https://doi.org/10.1007/s11745-005-1384-2

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11745-005-1384-2

Keywords

Navigation