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Lipoprotein lipase: structure, function and mechanism of action

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International Journal of Clinical and Laboratory Research

Summary

Lipoprotein lipase (LPL) plays a central role in the hydrolysis of circulating triglycerides present in chylomicrons, and very low density lipoproteins. The active form of the enzyme is a non-covalent homodimer which contains multiple functional domains required for normal hydrolytic activity including a catalytic domain, as well as sites involved in co-factor, heparin and lipid binding. Recent studies involving site-directed mutagenesis, the elucidation of the three dimensional crystallographic structure of different lipases, as well as analysis of the molecular defects that result in the expression of the familial chylomicronemia syndrome have provided new insights into the structure-function relationship of LPL. As a result, our understanding of structural domains involved in catalysis, heparin, lipid binding, and enzyme-cofactor interaction as well as the mechanism of action of LPL as an acylglycerol hydrolase has been greatly enhanced.

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References

  1. Brunzell JD. Familial lipoprotein lipase deficiency and other causes of the chylomicronemia syndrome. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic basis of inherited disease. New York: McGraw-Hill; 1989: 1165.

    Google Scholar 

  2. Havel RJ, Kane JP, Kashyap ML. Interchange of apolipoproteins between chylomicrons and high density lipoproteins during alimentary lipemia in man. J Clin Invest 1973; 52:32.

    PubMed  CAS  Google Scholar 

  3. Osborne JC Jr, Bengtsson-Olivecrona G, Lee NS, Olivecrona T. Studies on inactivation of lipoprotein lipase: role of the dimer to monomer dissociation. Biochemistry 1985; 24:5606.

    Article  PubMed  CAS  Google Scholar 

  4. Olivecrona T, Bengtsson-Olivecrona G, Osborne JC, Kempner ES. Molecular size of bovine lipoprotein lipase as determined by radiation inactivation. J Biol Chem 1985; 260:6888.

    PubMed  CAS  Google Scholar 

  5. Persson B, Jornvall H, Olivecrona T, Bengtsson-Olivecrona G. Lipoprotein lipases and vitellogenins in relation to the known three-dimensional structure of pancreatic lipase. FEBS Lett 1991; 288:33.

    Article  PubMed  CAS  Google Scholar 

  6. Derewenda ZS, Cambillau C. Effects of gene mutations in lipoprotein and hepatic lipases as interpreted by a molecular model of the pancreatic triglyceride lipase. J Biol Chem 1991; 266:23122.

    Google Scholar 

  7. Winkler FK, D'Arcy A, Hunziker W. Structure of human pancreatic lipase. Nature 1990; 343:771.

    Article  PubMed  CAS  Google Scholar 

  8. Santamarina-Fojo S, Brewer HB Jr. The familial hyperchylomicronemia syndrome. New insights into underlying genetic defects. JAMA 1991; 265:904.

    Article  PubMed  CAS  Google Scholar 

  9. Gagne C, Brum LD, Julien P, Moorjani S, Lupien PJ. Primary lipoprotein lipase activity deficiency: clinical investigation of a French Canadian population. Can Med Assoc J 1989; 140:405.

    CAS  Google Scholar 

  10. Santamarina-Fojo S. Genetic dyslipoproteinemias: role of lipoprotein lipase and apolipoprotein C-II. Curr Opin Lipidol 1992; 3:186.

    Article  CAS  Google Scholar 

  11. Lalouel JM, Wilson DE, Iverius PH. Lipoprotein lipase and hepatic triglyceride lipase: molecular and genetic aspects. Curr Opin Lipidol 1992; 3:86.

    Article  CAS  Google Scholar 

  12. Chimienti G, Capurso A, Resta F, Pepe G. A G→C change at the donor splice site of intron 1 causes lipoprotein lipase deficiency in a southern-Italian family. Biochem Biophys Res Commun 1992; 187:620.

    Article  PubMed  CAS  Google Scholar 

  13. Wilson DE, Hata A, Kwong LK, Lingam A, Shuhua J, Ridinger DN, Yeager C, Kaltenborn KC, Iverius PH, Lalouel JM. Mutations in exon 3 of the lipoprotein lipase gene segregating in a family with hypertriglyceridemia, pancreatitis, and non-insulin-dependent diabetes. J Clin Invest 1993; 92:203.

    PubMed  CAS  Google Scholar 

  14. Takagi A, Ikeda Y, Tsutsumi Z, Shoji T, Yamamoto A. Molecular studies on primary lipoprotein lipase (LPL) deficiency. One base deletion (G916) in exon 5 of LPL gene causes no detectable LPL protein due to the absence of LPL mRNA transcript. J Clin Invest 1992; 89:581.

    PubMed  CAS  Google Scholar 

  15. Sprecher DL, Kobayashi J, Rymaszewski M, Goldberg IJ, Harris BV, Bellet PS, Ameis D, Yunker RL, Black DM, Stein EA, Schotz MC, Wiginton DA. Trp64→nonsense mutation in the lipoprotein lipase gene. J Lipid Res 1992; 33:859.

    PubMed  CAS  Google Scholar 

  16. Hata A, Ridinger DN, Sutherland SD, Emi M, Kwong LK, Shuhua J, Lubbers A, Guy-Grand B, Basdevant A, Iverius P-H, Wilson DE, Lalouel J-M. Missense mutations in exon 5 of the human lipoprotein lipase gene. Inactivation correlates with loss of dimerization. J Biol Chem 1992; 267:20132.

    PubMed  CAS  Google Scholar 

  17. Ma Y, Wilson BI, Bijvoet S, Henderson HE, Cramb E, Roederer G, Ven Murthy MR, Julien P, Bakker HD, Kastelein JJP, Brunzell JD, Hayden MR. A missense mutation (Asp250→Asn) in exon 6 of the human lipoprotein lipase gene causes chylomicronemia in patients of different ancestries. Genomics 1992; 13:649.

    Article  PubMed  CAS  Google Scholar 

  18. Ishimura-Oka K, Semenkovich CF, Faustinella F, Goldberg IJ, Shachter N, Smith LC, Coleman T, Hide WA, Brown WV, Oka K, Chan L. A missense (Asp250→Asn) mutation in the lipoprotein lipase gene in two unrelated families with familial lipoprotein lipase deficiency. J Lipid Res 1992; 33:745.

    PubMed  CAS  Google Scholar 

  19. Kobayashi J, Nishida T, Ameis D, Stahnke G, Schotz MC, Hashimoto H, Fukamachi I, Shirai K, Saito Y, Yoshida S. A heterozygous mutations (the codon for Ser447—a stop codon) in lipoprotein lipase contributes to a defect in lipid interface recognition in a case with type I hyperlipidemia. Biochem Biophys Res Commun 1992; 182:70.

    Article  PubMed  CAS  Google Scholar 

  20. Gotoda T, Yamada N, Kawamura M, Kozaki K, Mori N, Ishibashi S, Shimano H, Takaku F, Yazaki Y, Furuichi Y, Murase T. Hetergeneous mutations in the human lipoprotein lipase gene in patients with familial lipoprotein lipase deficiency. J Clin Invest 1991; 88:1856.

    Article  PubMed  CAS  Google Scholar 

  21. Kobayashi J, Sasaki N, Tashiro J, Inadera H, Saito Y, Yoshida S. A missense mutation (Ala334→Thr) in exon 7 of the lipoprotein lipase gene in a case with type I hyperlipidemia. Biochem Biophys Res Commun 1993; 191:1046.

    Article  PubMed  CAS  Google Scholar 

  22. Previato L, Guardamagna O, Brunzell JD, Fojo SS, Brewer HB Jr. A novel missense mutation in the C-terminal domain of lipoprotein lipase leads to enzyme inactivation. Circulation 1992; 86:I-608.

    Google Scholar 

  23. Faustinella F, Smith LC, Semenkovich CF, Chan L. Structural and functional roles of highly conserved serines in human lipoprotein lipase. J Biol Chem 1991; 266:9481.

    PubMed  CAS  Google Scholar 

  24. Emmerich J, Beg OU, Peterson J, Previato L, Brunzell JD, Brewer HB Jr, Santamarina-Fojo S. Human lipoprotein lipase. Analysis of the catalytic triad by site-directed mutagenesis of Ser-132, Asp-156, and His-241. J Biol Chem 1992; 267:4161.

    PubMed  CAS  Google Scholar 

  25. Dichek HL, Parrott C, Ronan R, Brunzell JD, Brewer HB Jr, Santamarina-Fojo S. Functional characterization of a chimeric protein genetically engineered from human lipoprotein lipase and human hepatic lipase. J Lipid Res 1993; 34:1393.

    PubMed  CAS  Google Scholar 

  26. Wong H, Davis RC, Nikazy J, Seebart KE, Schotz MC. Domain exchange: characterization of a chimeric lipase of hepatic lipase and lipoprotein lipase. Proc Natl Acad Sci USA 1991; 88:11290.

    Article  PubMed  CAS  Google Scholar 

  27. Davis RC, Wong H, Nikazy J, Wang K, Han Q, Schotz MC. Chimeras of hepatic lipase and lipoprotein lipase. Domain localization of enzyme-specific properties. J Biol Chem 1992; 267:21499.

    PubMed  CAS  Google Scholar 

  28. Berryman DE, Bensadoun A. Site-directed mutagenesis of a putative heparin binding domain of avian lipoprotein lipase. J Biol Chem 1993; 268:3272.

    PubMed  CAS  Google Scholar 

  29. Hata A, Ridinger DN, Sutherland S, Emi M, Shuhua Z, Myers RL, Ren K, Cheng T, Inoue I, Wilson DE, Iverius P-H, Lalouel J-M. Binding of lipoprotein lipase to heparin. Identification of five critical residues in two distinct segments of the aminoterminal domain. J Biol Chem 1993; 268:8447.

    PubMed  CAS  Google Scholar 

  30. Lookene A, Bengtsson-Olivecrona G. Chymotryptic cleavage of lipoprotein lipase—identification of cleavage sites and functional studies of the truncated molecule. Eur J Biochem 1993; 213:185.

    Article  PubMed  CAS  Google Scholar 

  31. Dugi KA, Dichek HL, Talley GD, Brewer HB Jr, Santamarina-Fojo S. Human lipoprotein lipase: the loop covering the catalytic site is essential for interaction with lipid substrates. J Biol Chem 1992; 267:25086.

    PubMed  CAS  Google Scholar 

  32. Henderson HE, Ma Y, Liu MS, Clark-Lewis I, Maeder DL, Kastelein JJP, Brunzell JD, Hayden MR. Structure-function relationships of lipoprotein lipase: mutation analysis and mutagenesis of the loop region. J Lipid Res 1993; 34:1593.

    PubMed  CAS  Google Scholar 

  33. Tashiro J, Kobayashi J, Shirai K, Saito Y, Nakamura H, Morimoto Y, Yoshida S. Trypsin treatment may impair the interfacial activation action of lipoprotein lipase. J Biochem 1992; 111:509.

    PubMed  CAS  Google Scholar 

  34. Dugi KA, Dichek HL, Brewer HB Jr, Fojo SS. New insights into the structural basis for the different substrate specificities of hepatic lipase and lipoprotein lipase (abstract). Circulation 1993; 88:178.

    Google Scholar 

  35. Van Tilbeurgh H, Egloff MP, Martinez C, Rugani N, Verger R, Cambillau C. Interfacial activation of the lipase-procolipase complex by mixed micelles revealed by X-ray crystallography. Nature 1993; 362:814.

    Article  PubMed  Google Scholar 

  36. Wissler RW. Theories and new horizons in the pathogenesis of atherosclerosis and the mechanisms of clinical effects. Arch Pathol Lab Med 1992; 116:1281.

    PubMed  CAS  Google Scholar 

  37. Brzozowski AM, Derewenda U, Derewenda ZS, Dodson GG, Lawson DM, Turkenburg JP, Bjorkling F, Huge-Jensen B, Patkar SA, Thim L. A model for interfacial activation in lipases from the structure of a fungal lipase-inhibitor complex. Nature 1991; 351:491.

    Article  PubMed  CAS  Google Scholar 

  38. Derewenda U, Brzozowski AM, Lawson DM, Derewenda ZS. Catalysis at the interface: the anatomy of a conformational change in a triglyceride lipase. Biochemistry 1992; 31:1532.

    Article  PubMed  CAS  Google Scholar 

  39. Grochulski P, Li Y, Schrag JD, Bouthillier F, Smith P, Harrison D, Rubin B, Cygler M. Insights into interfacial activation from an open structure ofCandida rugosa lipase. J Biol Chem 1993; 268:12843.

    PubMed  CAS  Google Scholar 

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Santamarina-Fojo, S., Brewer, H.B. Lipoprotein lipase: structure, function and mechanism of action. Int J Clin Lab Res 24, 143–147 (1994). https://doi.org/10.1007/BF02592444

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