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Effect of ciprofibrate on the activation and oxidation of very long chain fatty acids

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Abstract

The effect of ciprofibrate, a hypolipidemic drug, was examined in the metabolism of palmitic (C16:0) and lignoceric (C24:0) acids in rat liver. Ciprofibrate is a peroxisomal proliferating drug which increases the number of peroxisomes. The palmitoyl-CoA ligase activity in peroxisomes, mitochondria and microsomes from ciprofibrate treated liver was 3.2, 1.9 and 1.5-fold higher respectively and the activity for oxidation of palmitic acid in peroxisomes and mitochondria was 8.5 and 2.3-fold higher respectively. Similarly, ciprofibrate had a higher effect on the metabolism of lignoceric acid. Treatment with ciprofibrate increased lignoceroyl-CoA ligase activity in peroxisomes, mitochondria and microsomes by 5.3, 3.3 and 2.3-fold respectively and that of oxidation of lignoceric acid was increased in peroxisomes and mitochondria by 13.4 and 2.3-fold respectively. The peroxisomal rates of oxidation of palmitic acid (8.5-fold) and lignoceric acid (13.4-fold) were increased to a different degree by ciprofibrate treatment. This differential effect of ciprofibrate suggests that different enzymes may be responsible for the oxidation of fatty acids of different chain length, at least at one or more step(s) of the peroxisomal fatty acid β-oxidation pathway.

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References

  1. Lazarow PB, de Duve C: Oxidizing System in Rat Liver Peroxisomes: Enhancement by Clofibrate. A Hipolipidemic Drug. Proc Natl Acad Sci USA 73: 2043–2046, 1976

    Google Scholar 

  2. Tolbert NE: Metabolic Pathways in Peroxisomes and Glyoxysomes. Ann Rev Biochem 50: 133–157, 1981

    Google Scholar 

  3. de Duve C: Microbodies in the Living Cell. Sci Amer 248: 52–62, 1983

    Google Scholar 

  4. Lazarow PB: Rat Liver Peroxisomes Catalyze the β-ox-idation of Fatty Acids. J Biol Chem 253: 1522–1528, 1978

    Google Scholar 

  5. Hashimoto T: Individual Peroxisomal β-oxidation Enzymes. Ann N Y Acad Sci 386: 5–12, 1982

    Google Scholar 

  6. Leighton F, Brandan E, Lazo O, Bronfman M: Subcellular Fractionation Studies on the Organization of Fatty Acid Oxidation by Liver Peroxisomes. Ann N Y Acad Sci 386: 62–78, 1982

    Google Scholar 

  7. Reddy JK, Rao MS, Lalwani MD, Reddy MK, Nemali MR, Alvares K: Induction of Hepatic Peroxisomes Proliferation of Xenobiotics. In: HD Fahimi and H Gus (eds.) Peroxisomes in Biology and Medicine, 1987, pp 255–262

  8. Osumi T, Hashimoto T: Subcellular Distribution of the Enzymes of the Fatty Acyl-CoA β-oxidation System and their Induction by Di (2-Ethylhexyl) Phthalate in Rat Liver. J Biochem 85: 131–139, 1979

    Google Scholar 

  9. Christiansen RZ, Christiansen EN, Bremer J: The Stimulation of Uracate Metabolism in Isolated Rat Hepatocytes by Rapeseed Oil and Hydrogenated Marine Oil-Containing Diets. Biochem Biophy Acta 573: 417–429, 1979

    Google Scholar 

  10. Ishii H, Fukermori N, Horie S, Suga T: Effects of Fat Content in the Diet on Hepatic Peroxisomes in Rat Liver. Biochim Biophys Acta 617: 1–11, 1980

    Google Scholar 

  11. Ishii H, Horie S, Suga T: Physiological Role of Peroxisomal Beta-Oxidation in Liver of Fasted Rats. J Biochem 87: 1855–1858, 1980

    Google Scholar 

  12. Horie S, Ishii H, Suga T: Changes in Peroxisomal Fatty Acid Oxidation in the Diabetic Rat Liver. J Biochem 90: 1691–1696, 1981

    Google Scholar 

  13. Hess R, Staubli W, Reiss W: Nature of the Hepatomegalic Effect Produced by Ethyl-Chlorophenoxy-Isobutirate in the Rat. Nature (London) 208: 856–858, 1965

    Google Scholar 

  14. Moody DE, Reddy JK: Morphometric Analysis of the Ultrastructural Changes in Rat Liver Induced by the Peroxisome Proliferator. J Cell Biol 71: 768–780, 1976

    Google Scholar 

  15. Kurup CKR, Aithal HN, Ramasarma T: Increased in Hepatic Mitochondria on Administration of Ethyl α-p-chlorophenoxyisobutyrate to the Rat. Biochem J 116: 773–779, 1970

    Google Scholar 

  16. Gear AL, Albert AD, Bedmarek JM: The Effect of the Hypocholesterolemic Drug Clofibrate on the Mitochondrial Biogenesis. J Biol Chem 249: 6495–6504, 1974

    Google Scholar 

  17. Singh I, Moser HW, Moser AE, Kishimoto Y: Lignoceric Acid is Oxidized in the Peroxisomes: Implications for the Zellweger Cerebro-Hepato-Renal Syndrome and Adrenoleukodystrophy. Biochem Biophys Res Commun 102: 1223–1229, 1981

    Google Scholar 

  18. Singh I, Moser HW, Moser AE, Kishimoto Y: Adrenoleukodystrophy: Impaired Oxidation of Very Long Fatty Acid in White Blood Cells, Cultured Skin Fibroblast and Amniocytes. Pediatr Res 18: 286–290, 1984

    Google Scholar 

  19. Singh I, Moser AE, Goldfischer S, Moser HW: Lignoceric Acid is Oxidized in the Peroxisomes: Implication for the Zellweger Cerebro-Hepato-Renal Syndrome and Adrenoleukodystrophy. Proc Natl Acad Sci USA 81: 4203–4207, 1984

    Google Scholar 

  20. Griffin JW, Goren E, Schaumberg HH, Engel WK, Loriaux L: Adrenomyeloneuropathy: A Probable Variant of Adrenoleukodystrophy. Neurology 27: 1107–1113, 1977

    Google Scholar 

  21. Moser HW, Moser AE, Singh I, O'Neill BP: Adrenoleukodystrophy: Survey of 303 Cases: Biochemistry, Diagnosis and Therapy. Ann Neurol 16: 628–641, 1984

    Google Scholar 

  22. Wander RJ, Van Roermund CW, Van Wigland MJ, Schutgens RB, Heikoop J, Van den Bosch H, Schram AW, Tager JM: Fatty Acid Beta-Oxidation in Relation to the Accumulation of Very Long Fatty Acids in Cultured Skin Fibroblasts from Patients with Zellweger Syndrome and Other Peroxisomal Disorders. J Clin Invest 80: 1778–1783, 1977

    Google Scholar 

  23. Poulus A, Singh H, Paton B, Sharp P, Derwas N: Accumulation and Defective β-Oxidation of Very Long Chain Fatty Acids in Zellweger's Syndrome, Adrenoleukodystrophy and Refsum's Disease Variants. Clin Genet 29: 397–408, 1986

    Google Scholar 

  24. Hashmi M, Stanley W, Singh I: Enzyme Defect in Fatty Acid β-oxidation System in X-Linked Childhood Adrenoleukodystrophy. FEBS Letts 196: 247–250, 1986

    Google Scholar 

  25. Lazo O, Contreras M, Hashmi M, Stanley W, Irazu C, Singh I: Peroxisomal Lignoceroyl-CoA Ligase Deficiency in Childhood Adrenoleukodystrophy and Adrenomieloneuropathy. Proc Natl Acad Sci USA. 85: 7647–7651, 1988

    Google Scholar 

  26. Lazo O, Contreras M, Bhusdan A, Stanley W, Singh I: Adrenoleukodystrophy: Impaired Oxidation of Fatty Acids Due to Peroxisomal Lignoceroyl-CoA Ligase Deficiency. Arch Biochem Biophys 270: 722–728, 1989

    Google Scholar 

  27. Wanders RJA, Van-Roermund CWT, Van Wijland MJA, Schutgens RBH, Van den Bosch H, Scham AW, Tager JM: Direct Demonstration that the Deficient Oxidation of Very Long Chain Fatty Acids in X-Linked Adrenoleukodystrophy is Due to an Impaired Ability of Peroxisomes to Active Very Long Chain Fatty Acids. Biochem Biophy Res Commun 153: 618–624, 1988

    Google Scholar 

  28. Moser AE, Singh I, Brown FR, Solish GI, Kelley RJ, Benke PJ, Moser HW: The Cerebro-Hepato-Renal (Zellweger) Syndrome: Increased Levels and Impaired Degradation of Very Long Chain Fatty Acids and their Use in Prenatal Diagnosis. New Engl J Med 310: 1141–1146, 1984

    Google Scholar 

  29. Igarashi M, Schaumberg HH, Powers JM, Kishimoto Y, Kolodny E, Suzuki K: Fatty Acid Abnormalities in Adrenoleukodystrophy. J Neurochem 26: 851–860, 1976

    Google Scholar 

  30. Yoshida Y, Singh I: Effect of Clofibrate on the Peroxisomal Lignoceroyl-CoA Ligase. Biochemical Med. and Metabolic Biology 43: 22–29, 1990

    Google Scholar 

  31. Hoshi M, Kishimoto Y: Synthesis of Cerebronic Acid from Lignoceric Acid by Rat Brain Preparation. J Biol Chem 248: 4123–4130, 1973

    Google Scholar 

  32. Akamura S, Kishimoto Y: Synthesis of Ceramides and Cerebrosides Containing both α-Hydroxy and Nonhydroxy fatty Acids from Lignoceroyl-CoA in Rat Liver Microsomes. J Biol Chem 254: 1050–1056, 1979

    Google Scholar 

  33. Leighton F, Poole B, Beaufay H, Baudhuin PB: The Large Scale Separation of Peroxisomes, Mitochondria and Lysosomes from the Livers of Rats Injected with Triton WR-1339. J Cell Biol 37: 482–512, 1968

    Google Scholar 

  34. Cooperstein SJ, Lazarow P: Microspectrophotometric method for the determination of cytochrome oxidase. J Biol Chem 189: 655–670, 1971

    Google Scholar 

  35. Beaufay H, Amar-Cortesec A, Feytmans E, Thines-Sempoux D, Wibo M, Robbi MN, Berthet T: Analytical Study of Microsomes and Isolated Subcellular Membranes from Rat liver. J Cell Biol 61: 188–200, 1974

    Google Scholar 

  36. Baudhuin P, Beaufay Y, Li O Rahman, Sellinger Z, Wattiaux R, Jacques P, de Duve C: Tissue fractionation Studies. Biochem J 92: 179–184, 1964

    Google Scholar 

  37. Sellinger OZ, Beaufay H, Jacques P, Doyer A, de Duve C: Tissue Fractionation Studies. Biochem J 74: 450–456, 1960

    Google Scholar 

  38. Bradford M: 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, 1976

    Article  CAS  PubMed  Google Scholar 

  39. Singh I, Singh RP, Bhushan A, Singh AK: Lignoceroyl-CoA Ligase Activity in Rat Brain Microsomel Fraction: Topographical Localization and Effect of Detergents and α-cyclodextrin. Arch Biochem Biophys 236: 418–426, 1985

    Google Scholar 

  40. Folch J, Lees M, Shoane-Stanley GH: A Simple Method for the Isolation and Purification of Total Lipids from Animal Tissues. J Biol Chem 226: 497–509, 1975

    Google Scholar 

  41. Singh I, Kishimoto Y: Effect of Cyclodextrins on the Solubilization of Lignoceric Acid, Ceramide and Cerebroside and on the Enzymatic Reactions Involving these Compounds. J Lipid Res 24: 662–665, 1983

    Google Scholar 

  42. Inestrosa NC, Bronfman M, Leighton F: Detection of Peroxisomal Fatty Acyl-Coenzyme A Oxidase Activity. Biochem J 182: 777–788, 1979

    Google Scholar 

  43. Osmundsen H, Thomassen MS, Hiltunen JK, Berge RK: Physiological Role of Peroxisomal Beta-Oxidation. In: Fahimi and Sies (eds) Peroxisomes in Biology and Medicine, Berlin, Springer-Verlag, 1987, pp 152–162

    Google Scholar 

  44. Miyazawa S, Hashimoto T, Yokota S: Identity of Long Chain Acyl-Coenzyme. A Synthetase of Microsomes, Mitochondria and Peroxisomes in Rat Liver. J Biochem 98: 723–733, 1985

    Google Scholar 

  45. Singh I, Bhushan A, Relan NK, Hashimoto T: Acyl-CoA Ligases from Brain Microsomes: An Immunochemical Study. Biochem Biophys Acta 963: 509–514, 1989

    Google Scholar 

  46. Lazo O, Contreras M, Singh I: Topographical Localization of Peroxisomal Acyl-CoA Ligases: Differential Localization of Palmitoyl-CoA and Lignoceroyl-CoA Ligases. Biochemistry 29: 3981–3986, 1990

    Google Scholar 

  47. Singh I, Johnson GH, Brown FR: Peroxisomal Disorders: A Biochemical Classification. Am J Dis Child 142: 1297–1301, 1988

    Google Scholar 

  48. Moser HW, Moser AW: Adrenoleukodystrophy (X-linked): In: CR Scriver, AL Beaudet, WS Sly and D Valle (eds.) The Metabolic Basis of Inherited Disease. McGraw-Hill NY, 1989, pp 58–1532

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Lazo, O., Contreras, M. & Singh, I. Effect of ciprofibrate on the activation and oxidation of very long chain fatty acids. Mol Cell Biochem 100, 159–167 (1991). https://doi.org/10.1007/BF00234165

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