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Regulation of phosphatidic acid phosphohydrolase 1 by fatty acids

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Lipids

Abstract

In the starved state and during metabolic stress, free fatty acids (FFA) are the principal hepatic energy supply, undergoing β-oxidation. Accordingly, it appears paradoxical that H-A have been reported to increase the liver's esterification capacity by translocating the rate-limiting enzyme phosphatidic acid phosphohydrolase (PAP-1) from the cytosol to the endoplasmic reticulum. We have therefore investigated the regulation of rat liver PAP-1. Oleic acid inhibited PAP activity in all subcellular fractions, with PAP-1 activity in cytosol being the most sensitive. Inhibition was also observed with oleoyl-CoA, linoleate, and palmitate. Fatty acids and their derivatives show detergent effects at high concentrations, and such effects can lead to enzyme inhibition. Inhibition by oleate, however, was reversed by phosphatidic acid and albumin and exhibited sigmoidal kinetics. These results demonstrate that PAP-1 is reversibly inhibited by FFA and their CoA esters, which may play a role in directing hepatic FFA to β-oxidation during times of increased energy demand.

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Abbreviations

BSA:

bovine serum albumin

DAG:

diacylglycerol

DDT:

dithiothreitol

ER:

endoplasmic reticulum

FFA:

free fatty acid

NEM:

N-ethylmaleimide

PA:

phosphatidic acid

PAP:

phosphatidic acid phosphohydrolase

TAG:

triacylglycerol

References

  1. Tijburg, L.B.M., Geelen, M.J.H., and van Golde, L.M.G. (1989) Regulation of the Biosynthesis of Triacylglycerol Phosphatidylcholine and Phosphatidylethanolamine in the Liver, Biochim. Biophys. Acta 1004, 1–19.

    PubMed  CAS  Google Scholar 

  2. Brindley, D.N., and Waggoner, D.W. (1998) Mammalian Lipid Phosphate Phosphohydrolases, J. Biol. Chem. 273, 23281–24284.

    Article  Google Scholar 

  3. Day, C.P., James, O.F.W., Brown, A.J.M., Bennett, M.K., Fleming, I.N., and Yeaman, S.J. (1993) The Activity of the Metabolic Form of Hepatic Phosphatidate Phosphohydrolase Correlates with the Severity of Alcoholic Fatty Liver in Human Beings, Hepatology 18, 832–838.

    Article  PubMed  CAS  Google Scholar 

  4. Jamal, Z., Martin, A., Gomez-Munoz, A., and Brindley, D.N. (1991) Plasma Membrane Fractions from Rat Liver Contain a Phosphatidate Phosphohydrolase Distinct from That in the Endoplasmic Reticulum and Cytosol, J. Biol. Chem. 266, 2988–2996.

    PubMed  CAS  Google Scholar 

  5. Day, C.P., and Yeaman, S.J. (1992) Physical Evidence for the Presence of Two Forms of Phosphatidate Phosphohydrolase in Rat Liver, Biochim. Biophys. Acta 1127, 87–94.

    PubMed  CAS  Google Scholar 

  6. Fleming, I.N., and Yeaman, S.J. (1995) Purification and Characterization of N-Ethylmaleimide-Sensitive Phosphatidic Acid Phosphohydrolase (PAP2) from Rat Liver, Biochem. J. 308, 983–989.

    PubMed  CAS  Google Scholar 

  7. Waggoner, D.W., Gomez-Munoz, A., Dewald, J., and Brindley, D.N. (1996) Phosphatidate Phosphohydrolase Catalyzes the Hydrolysis of Ceramide 1-Phosphate, Lysophosphatidate, and Sphingosine 1-Phosphate, J. Biol. Chem. 271, 16506–16509.

    Article  PubMed  CAS  Google Scholar 

  8. Kai, M., Wada, I., Imai, S., Sakane, F., and Kanoh, H. (1997) Cloning and Characterization of Two Human Isozymes of Mg2+-Independent Phosphatidic Acid Phosphatase, J. Biol. Chem. 272, 24572–24578.

    Article  PubMed  CAS  Google Scholar 

  9. Brindley, D.N. (1985) Intracellular Translocation of Phosphatidate Phosphohydrolase and Its Possible Role in the Control of Glycerolipid Synthesis, Prog. Lilids Res. 23, 115–133.

    Article  CAS  Google Scholar 

  10. Cascales, C., Mangiapane, E.H., and Brindley, D.N. (1984) Oleic Acid Promotes the Activation and Translocation of Phosphatidate Phosphohydrolase from the Cytosol to Particulate Fractions of Isolated Rat Hepatocyte, Biochem. J. 219, 911–916.

    PubMed  CAS  Google Scholar 

  11. Martin-Sanz, P., Hopewell, R., and Brindley, D.N. (1984) Long-Chain Fatty Acids and Their Acyl-CoA Esters Cause the Translocation of Phosphatidate Phosphohydrolase from the Cytosolic to the Microsomal Fraction of Rat Liver, FEBS Lett. 175, 284–288.

    Article  PubMed  CAS  Google Scholar 

  12. Martin-Sanz, P., Hopewell, R., and Brindley, D.N. (1985) Spermine Promotes the Translocation of Phosphatidate Phosphohydrolase from the Cytosol to the Microsomal Fraction of Rat Liver and It Enhances the Effects of Oleate in This Respect, FEBS Lett. 179, 262–266.

    Article  PubMed  CAS  Google Scholar 

  13. Hopewell, R., Martin-Sanz, P., Martin, A., Saxton, J., and Brindley, D.N. (1985) Regulation of the Translocation of Phosphatidate Phosphohydrolase Between the Cytosol and the Endoplasmic Reticulum of Rat Liver, Biochem. J. 232, 485–491.

    PubMed  CAS  Google Scholar 

  14. Gomez-Munoz, A., Hamza, E.H., and Brindley, D.N. (1992) Effects of Sphingosine, Albumin and Unsaturated Fatty Acids on the Activation and Translocation of Phosphatidate Phosphohydrolases in Rat Hepatocytes, Biochim. Biophys. Acta 1127, 49–56.

    PubMed  CAS  Google Scholar 

  15. Asiedu, D., Skorve, J., Demoz, A., Willumsen, N., and Berge, R.K. (1992) Relationship Between Translocation of Long-Chain Acyl-CoA Hydrolase, Phosphatidate Phosphohydrolase and CTP:Phosphocholine Cytidyltransferase and the Synthesis of Triglycerides and Phosphatidylcholine in Rat Liver, Lipids 27, 241–247.

    PubMed  CAS  Google Scholar 

  16. Gomez-Munoz, A., Hatch, G.M., Martin, A., Jamal, Z., Vance, D.E., and Brindley, D.N. (1992) Effects of Okadaic Acid on the Activities of Two Distinct Phosphatidate Phosphohydrolases in Rat Hepatocytes, FEBS Lett. 301, 103–106.

    Article  PubMed  CAS  Google Scholar 

  17. Cheng, C.H.K., and Saggerson, E.D. (1978) Rapid Effects of Noradrenaline on Mg2+-Dependent Phosphatidate Phosphohydrolase Activity in Rat Adipocytes, FEBS Lett. 87, 65–68.

    Article  PubMed  CAS  Google Scholar 

  18. Cheng, C.H.K., and Saggerson, E.D. (1978) Rapid Antagonistic Actions of Noradrenaline and Insulin on Rat Adipocyte Phosphatidate Phosphohydrolase Activity, FEBS Lett. 93, 120–124.

    Article  PubMed  CAS  Google Scholar 

  19. Fleming, I.N., and Yeaman, S.J. (1995) Subcellular Distribution of N-Ethylmaleimide-Sensitive and Insensitive Phosphatidic Acid Phosphohydrolase in Rat Brain, Biochim. Biophys. Acta 1254, 161–168.

    PubMed  Google Scholar 

  20. Duggleby, R.G. (1981) A Nonlinear Regression Program for Small Computers, Anal. Biochem. 110, 9–18.

    Article  PubMed  CAS  Google Scholar 

  21. Monod, J., Wyman, J., and Changeux, J.-P. (1965) On the Nature of Allosteric Transitions: A Plausible Model, J. Mol. Biol. 12, 88–117.

    Article  PubMed  CAS  Google Scholar 

  22. Ide, T., and Ontko, J.A. (1981) Increased Secretion of Very Low Density Lipoprotein Triglyceride Following Inhibition of Long Chain Fatty Acid Oxidation in Isolated Rat Liver, J. Biol. Chem. 256, 10247–10255.

    PubMed  CAS  Google Scholar 

  23. Ontko, J.A. (1972) Metabolism of Free Fatty Acids in Isolated Liver Cells. Factors Affecting the Partition Between Esterification and Oxidation, J. Biol. Chem. 247, 1788–1800.

    PubMed  CAS  Google Scholar 

  24. Martin, A., Hopowell, R., Martin-Sanz, P., Morgan, J.E., and Brindley, D.N. (1986) Relationship Between the Displacement of Phosphatidate Phosphohydrolase from the Membrane-Associated Compartment by Chlorpromazine and the Inhibition of the Synthesis of Triacylglycerol and Phosphatidylcholine in Rat Hepatocytes, Biochim. Biophys. Acta 876, 581–591.

    PubMed  CAS  Google Scholar 

  25. Freeman, M., and Mangiapane, E.H. (1989) Translocation to Rat Liver Mitchondria of Phosphatidate Phosphohydrolase, Biochem. J. 263, 589–595.

    PubMed  CAS  Google Scholar 

  26. Besterman, J.M., Pollenz, R.S., Booker, E.L., and Cuatrecasas, P. (1986) Diacylglycerol-Induced Translocation of Diacylglycerol Kinase: Use of Affinity-Purified Enzyme in a Reconstitution System, Proc. Natl. Acad. Sci. USA 83, 9378–9382.

    Article  PubMed  CAS  Google Scholar 

  27. Day, C.P., and Yeaman, S.J. (1994) The Biochemistry of Alcohol-Induced Fatty Liver, Biochim. Biophys. Acta 1215, 33–48.

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. School of Biochemistry and Genetics, University of Newcastle upon Tyne, NE2 4HH, Newcastle upon Tyne, UK

    Richard Virden & Stephen J. Yeaman

  2. Centre for Liver Research, Medical School, University of Newcastle upon Tyne, NE2 4HH, Newcastle upon Tyne, UK

    Christopher P. Day & Stephen J. Yeaman

  3. Facute des Sciences et Techniques, University Cadi Ayyad, Beni-Mellal, Morocco

    Noureddine Elabbadi

Authors
  1. Noureddine Elabbadi
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  2. Christopher P. Day
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  3. Richard Virden
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  4. Stephen J. Yeaman
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Correspondence to Noureddine Elabbadi.

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Elabbadi, N., Day, C.P., Virden, R. et al. Regulation of phosphatidic acid phosphohydrolase 1 by fatty acids. Lipids 37, 69–73 (2002). https://doi.org/10.1007/s11745-002-0865-7

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  • DOI: https://doi.org/10.1007/s11745-002-0865-7

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