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Gene Review

LPL  -  lipoprotein lipase

Homo sapiens

Synonyms: HDLCQ11, LIPD, Lipoprotein lipase
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Disease relevance of LPL


Psychiatry related information on LPL


High impact information on LPL

  • Lipoprotein lipase plays a central role in lipid metabolism and the gene that encodes this enzyme (LPL) is a candidate susceptibility gene for cardiovascular disease [9].
  • If LPL is a typical human gene, the pattern of sequence variation that exists in introns as well as exons, even for the small number of samples considered here, will present challenges for the identification of sites, or combinations of sites, that influence variation in risk of disease in the population at large [9].
  • Here we report the complete sequence of a fraction of the LPL gene for 71 individuals (142 chromosomes) from three populations that may have different histories affecting the organization of the sequence variation [9].
  • DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene [9].
  • RESULTS: All four patients had a profound functional deficiency of lipoprotein lipase with a reduced enzymatic mass due to missense mutations on both alleles of the lipoprotein lipase gene [10].

Chemical compound and disease context of LPL

  • The dose of heparin (100 I.U./kg body weight) used intravenously to get maximal release of both HL and LPL was the same in patients and in healthy individuals [11].
  • It is plausible that a low LPL activity contributes to premature atherosclerosis as observed in insulin resistance and type 2 diabetes mellitus, but the effects of high HL activity and altered plasma cholesterol esterification on atherosclerosis development are uncertain [12].
  • The lack of effect on lipoprotein lipase activity and regulation in combination with significant improvements of other aspects of lipid and glucose transport is consistent with the view that alterations in LPL activity and regulation may represent an early and possibly primary defect in the development of obesity [13].
  • METHODS: We compared LPL activity and the presence of four common variants in the LPL gene (Asp 9 Asn (exon 2), Gly 188 Glu (exon 5), Asn 291 Ser (exon 6) and Ser 447 Ter (exon 9)) in a group of 34 patients of whom 17 presented diabetes mellitus [14].
  • Dyslipoproteinaemia in hypothyroidism of pituitary origin: effects of L-thyroxine substitution on lipoprotein lipase, hepatic lipase, and on plasma lipoproteins [15].

Biological context of LPL

  • The addition of ApoC-III-2 resulted in a decreased rate of lipolysis of human very low density lipoproteins by LPL [16].
  • We previously demonstrated that two amino acid substitutions in LPL, the Asn291-Ser and the Asp9-Asn, are associated with elevated triglycerides and lower HDL cholesterol and are present with greater frequency in coronary artery disease (CAD) patients than in normolipidemic control subjects [1].
  • CONCLUSIONS: We conclude that the LPL Ser447-Stop mutation has a significant positive effect on LPL activity and HDL cholesterol and triglyceride levels and that certain subgroups of CAD patients carrying the Ser447-Stop mutation will have less adverse metabolic effects when placed on beta-blockers [1].
  • Finally, HL is more active than LPL in the hydrolysis of phospholipid substrates [17].
  • The expression of both apo E and LPL in atherosclerotic lesions but not in normal intima suggest that these molecules play a role in lipid metabolism in atherosclerosis [18].

Anatomical context of LPL

  • Two cytokines known to diminish adipose tissue LPL activity were studied to see how their effects were regulated [19].
  • This report describes the cloning of the mouse LPL gene from which probes were derived to study the regulation of LPL synthesis in the 3T3-L1 adipocyte cell culture system [19].
  • Half of the regions with non-foam cell macrophages expressed neither apo E nor LPL messenger RNA, whereas 86% of macrophage foam cell-containing regions contained both messenger RNAs [18].
  • We examined the role of LPL in modulating tumor necrosis factor-alpha (TNF-alpha)- and interferon-gamma (IFN-gamma)-mediated inflammatory cytokine signal transduction pathways in human aortic endothelial cells (HAECs) [20].
  • In contrast, addition of the 39-kDa receptor-associated protein (RAP) caused a 43% decrease in the LPL-dependent LDL degradation in non-up-regulated fibroblasts [21].

Associations of LPL with chemical compounds

  • LPL activity correlated indirectly with lipemia, triglyceride content of HDL2, HL activity, and levels of HDL2 but not of HDL3 [22].
  • Cyanogen bromide fragments of apoC-II corresponding to residues 1--9 and 10--59 had little ability to activate LPL [23].
  • After insulin and dexamethasone were added, LPL activity and mRNA levels rose in parallel [19].
  • Despite their effect on LPL activity, substitutions of Ser-132, Asp-156, and His-241 did not change either the heparin affinity or lipid binding properties of the mutant LPL [24].
  • HL and LPL bind to vascular endothelium, presumably by interaction with cell surface heparan sulfate proteoglycans [17].

Physical interactions of LPL

  • Crosslinking experiments on cells with 125I-labeled apoE liposomes or lipoprotein lipase showed that both proteins were able to bind to LRP on the cell surface [25].
  • Also, LPL-induced binding to cells was blocked by an anti-LPL monoclonal antibody but not by antibodies that are known to block apolipoprotein E- or B-100-mediated binding to low density lipoprotein (LDL) receptors [26].
  • These studies confirm that the VLDL receptor binds to and mediates the catabolism of LpL and uPA.PAI-1 complexes [27].
  • However, we found that gp330 (purified from human or rat) bound the lipolytic enzyme lipoprotein lipase (LPL) with high affinity (Kd = 6.1 and 2.7 nM, respectively) [28].
  • These results indicated that neither TG solubility nor amount of apoC-II binding were determinate factors in LPL-mediated lipolysis under physiological conditions [29].

Enzymatic interactions of LPL


Regulatory relationships of LPL

  • To determine the minimal sequence requirements for activation, we have prepared both native and synthetic fragments of apoC-II and tested them for their ability to activate LPL [23].
  • LPL significantly suppressed TNF-alpha-induced gene expression, and this suppression was reversed by tetrahydrolipstatin and heparinase [20].
  • Furthermore, LPL promoted binding of 125I-lipoproteins to highly purified LRP in a solid-phase assay [26].
  • Thus, the VLDL receptor may play a unique role on the vascular endothelium in lipoprotein catabolism by regulating levels of LpL and in the regulation of fibrinolysis by facilitating the removal of urokinase complexed with its inhibitor [27].
  • Consistent with this possibility, we found that LPL promoted in vitro binding of 125I-lipoproteins to gp330 [28].

Other interactions of LPL

  • The latter correlated positively with LPL activity and HDL2 levels, and, inversely, with HL activity, lipemia, and triglyceride content of HDL2 [22].
  • Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III [16].
  • These studies suggest that the maximal activation of LPL by apoC-II requires a minimal sequence contained within residues 55--78 [23].
  • The effect of recombinant human cachectin tumor necrosis factor on LPL mRNA levels was shown by nuclear run-on experiments to be exerted transcriptionally [19].
  • In pulse-chase experiments, addition of LPL during the chase period produced a decrease in secretion of apoprotein E from human monocyte-derived macrophages, from the human monocytic THP1 cell line, and from J774 cells transfected to constitutively express a human apo E cDNA [32].

Analytical, diagnostic and therapeutic context of LPL


  1. Genetic variant showing a positive interaction with beta-blocking agents with a beneficial influence on lipoprotein lipase activity, HDL cholesterol, and triglyceride levels in coronary artery disease patients. The Ser447-stop substitution in the lipoprotein lipase gene. REGRESS Study Group. Groenemeijer, B.E., Hallman, M.D., Reymer, P.W., Gagné, E., Kuivenhoven, J.A., Bruin, T., Jansen, H., Lie, K.I., Bruschke, A.V., Boerwinkle, E., Hayden, M.R., Kastelein, J.J. Circulation (1997) [Pubmed]
  2. Autoantibodies to lipoprotein lipase and dyslipidemia in systemic lupus erythematosus. Reichlin, M., Fesmire, J., Quintero-Del-Rio, A.I., Wolfson-Reichlin, M. Arthritis Rheum. (2002) [Pubmed]
  3. Decreased plasma lipoprotein lipase in hypoadiponectinemia: an association independent of systemic inflammation and insulin resistance. von Eynatten, M., Schneider, J.G., Humpert, P.M., Rudofsky, G., Schmidt, N., Barosch, P., Hamann, A., Morcos, M., Kreuzer, J., Bierhaus, A., Nawroth, P.P., Dugi, K.A. Diabetes Care (2004) [Pubmed]
  4. Gender specific associations of the Trp64Arg mutation in the beta3-adrenergic receptor gene with obesity-related phenotypes in a Mediterranean population: interaction with a common lipoprotein lipase gene variation. Corella, D., Guillén, M., Portolés, O., Sorlí, J.V., Alonso, V., Folch, J., Sáiz, C. J. Intern. Med. (2001) [Pubmed]
  5. Lipoprotein lipase mutations and Alzheimer's disease. Baum, L., Chen, L., Masliah, E., Chan, Y.S., Ng, H.K., Pang, C.P. Am. J. Med. Genet. (1999) [Pubmed]
  6. Roles for lipoprotein lipase in Alzheimer's disease: an association study. Baum, L., Wiebusch, H., Pang, C.P. Microsc. Res. Tech. (2000) [Pubmed]
  7. The lipoprotein lipase S447X polymorphism and plasma lipids: interactions with APOE polymorphisms, smoking, and alcohol consumption. Lee, J., Tan, C.S., Chia, K.S., Tan, C.E., Chew, S.K., Ordovas, J.M., Tai, E.S. J. Lipid Res. (2004) [Pubmed]
  8. Food deprivation increases post-heparin lipoprotein lipase activity in humans. Ruge, T., Svensson, A., Eriksson, J.W., Olivecrona, T., Olivecrona, G. Eur. J. Clin. Invest. (2001) [Pubmed]
  9. DNA sequence diversity in a 9.7-kb region of the human lipoprotein lipase gene. Nickerson, D.A., Taylor, S.L., Weiss, K.M., Clark, A.G., Hutchinson, R.G., Stengård, J., Salomaa, V., Vartiainen, E., Boerwinkle, E., Sing, C.F. Nat. Genet. (1998) [Pubmed]
  10. Premature atherosclerosis in patients with familial chylomicronemia caused by mutations in the lipoprotein lipase gene. Benlian, P., De Gennes, J.L., Foubert, L., Zhang, H., Gagné, S.E., Hayden, M. N. Engl. J. Med. (1996) [Pubmed]
  11. Hepatic lipase and lipoprotein lipase in postheparin plasma in liver disease. relations to plasma proteins. Sauar, J., Skrede, S., Blomhoff, J.P. Clin. Chim. Acta (1978) [Pubmed]
  12. Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus. de Vries, R., Borggreve, S.E., Dullaart, R.P. Clin. Lab. (2003) [Pubmed]
  13. Effects of weight reduction on plasma lipoproteins and adipose tissue metabolism in obese subjects. Sörbris, R., Petersson, B.G., Nilsson-Ehle, P. Eur. J. Clin. Invest. (1981) [Pubmed]
  14. Lipoprotein lipase activity and common gene variants in severely hypertriglyceridemic patients with and without diabetes. Chadarevian, R., Foubert, L., Beucler, I., Kottler, M.L., Raisonnier, A., Ajlouni, A., Giral, P., Turpin, G., Bruckert, E. Horm. Res. (2003) [Pubmed]
  15. Dyslipoproteinaemia in hypothyroidism of pituitary origin: effects of L-thyroxine substitution on lipoprotein lipase, hepatic lipase, and on plasma lipoproteins. Valdemarsson, S., Hedner, P., Nilsson-Ehle, P. Acta Endocrinol. (1983) [Pubmed]
  16. Modulation of lipoprotein lipase activity by apolipoproteins. Effect of apolipoprotein C-III. Wang, C.S., McConathy, W.J., Kloer, H.U., Alaupovic, P. J. Clin. Invest. (1985) [Pubmed]
  17. Chimeras of hepatic lipase and lipoprotein lipase. Domain localization of enzyme-specific properties. Davis, R.C., Wong, H., Nikazy, J., Wang, K., Han, Q., Schotz, M.C. J. Biol. Chem. (1992) [Pubmed]
  18. Apolipoprotein E localization in human coronary atherosclerotic plaques by in situ hybridization and immunohistochemistry and comparison with lipoprotein lipase. O'Brien, K.D., Deeb, S.S., Ferguson, M., McDonald, T.O., Allen, M.D., Alpers, C.E., Chait, A. Am. J. Pathol. (1994) [Pubmed]
  19. Recombinant human cachectin/tumor necrosis factor but not interleukin-1 alpha downregulates lipoprotein lipase gene expression at the transcriptional level in mouse 3T3-L1 adipocytes. Zechner, R., Newman, T.C., Sherry, B., Cerami, A., Breslow, J.L. Mol. Cell. Biol. (1988) [Pubmed]
  20. Differential effects of lipoprotein lipase on tumor necrosis factor-alpha and interferon-gamma-mediated gene expression in human endothelial cells. Kota, R.S., Ramana, C.V., Tenorio, F.A., Enelow, R.I., Rutledge, J.C. J. Biol. Chem. (2005) [Pubmed]
  21. Cellular differences in lipoprotein lipase-mediated uptake of low density lipoproteins. Obunike, J.C., Edwards, I.J., Rumsey, S.C., Curtiss, L.K., Wagner, W.D., Deckelbaum, R.J., Goldberg, I.J. J. Biol. Chem. (1994) [Pubmed]
  22. High density lipoprotein2. Relationship of the plasma levels of this lipoprotein species to its composition, to the magnitude of postprandial lipemia, and to the activities of lipoprotein lipase and hepatic lipase. Patsch, J.R., Prasad, S., Gotto, A.M., Patsch, W. J. Clin. Invest. (1987) [Pubmed]
  23. Activation of lipoprotein lipase by native and synthetic fragments of human plasma apolipoprotein C-II. Kinnunen, P.K., Jackson, R.L., Smith, L.C., Gotto, A.M., Sparrow, J.T. Proc. Natl. Acad. Sci. U.S.A. (1977) [Pubmed]
  24. Human lipoprotein lipase. Analysis of the catalytic triad by site-directed mutagenesis of Ser-132, Asp-156, and His-241. Emmerich, J., Beg, O.U., Peterson, J., Previato, L., Brunzell, J.D., Brewer, H.B., Santamarina-Fojo, S. J. Biol. Chem. (1992) [Pubmed]
  25. Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein. Beisiegel, U., Weber, W., Bengtsson-Olivecrona, G. Proc. Natl. Acad. Sci. U.S.A. (1991) [Pubmed]
  26. Lipoprotein lipase induces catabolism of normal triglyceride-rich lipoproteins via the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor in vitro. A process facilitated by cell-surface proteoglycans. Chappell, D.A., Fry, G.L., Waknitz, M.A., Muhonen, L.E., Pladet, M.W., Iverius, P.H., Strickland, D.K. J. Biol. Chem. (1993) [Pubmed]
  27. The very low density lipoprotein receptor mediates the cellular catabolism of lipoprotein lipase and urokinase-plasminogen activator inhibitor type I complexes. Argraves, K.M., Battey, F.D., MacCalman, C.D., McCrae, K.R., Gåfvels, M., Kozarsky, K.F., Chappell, D.A., Strauss, J.F., Strickland, D.K. J. Biol. Chem. (1995) [Pubmed]
  28. Glycoprotein 330, a member of the low density lipoprotein receptor family, binds lipoprotein lipase in vitro. Kounnas, M.Z., Chappell, D.A., Strickland, D.K., Argraves, W.S. J. Biol. Chem. (1993) [Pubmed]
  29. Effects of sphingomyelin and cholesterol on lipoprotein lipase-mediated lipolysis in lipid emulsions. Arimoto, I., Saito, H., Kawashima, Y., Miyajima, K., Handa, T. J. Lipid Res. (1998) [Pubmed]
  30. Lipoprotein lipase prevents the hepatic lipase-induced reduction in particle size of high density lipoproteins during incubation of human plasma. Newnham, H.H., Hopkins, G.J., Devlin, S., Barter, P.J. Atherosclerosis (1990) [Pubmed]
  31. Purification and characterization of lipoprotein lipase and hepatic triglyceride lipase from human postheparin plasma: production of monospecific antibody to the individual lipase. Ikeda, Y., Takagi, A., Yamamoto, A. Biochim. Biophys. Acta (1989) [Pubmed]
  32. Lipoprotein lipase reduces secretion of apolipoprotein E from macrophages. Lucas, M., Iverius, P.H., Strickland, D.K., Mazzone, T. J. Biol. Chem. (1997) [Pubmed]
  33. Cachectin/tumor necrosis factor decreases human adipose tissue lipoprotein lipase mRNA levels, synthesis, and activity. Fried, S.K., Zechner, R. J. Lipid Res. (1989) [Pubmed]
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