A novel endothelial-derived lipase that modulates HDL metabolism


High-density lipoprotein (HDL) cholesterol levels are inversely associated with risk of atherosclerotic cardiovascular disease1. At least 50% of the variation in HDL cholesterol levels is genetically determined2,3, but the genes responsible for variation in HDL levels have not been fully elucidated. Lipoprotein lipase (LPL) and hepatic lipase (HL), two members of the triacylglyerol (TG) lipase family, both influence HDL metabolism2,4,5,6 and the HL (LIPC) locus has been associated with variation in HDL cholesterol levels in humans7,8. We describe here the cloning and in vivo functional analysis of a new member of the TG lipase family. In contrast to other family members, this new lipase is synthesized by endothelial cells in vitro and thus has been termed endothelial lipase (encoded by the LIPG gene). EL is expressed in vivo in organs including liver, lung, kidney and placenta, but not in skeletal muscle. In contrast to LPL and HL, EL has a lid of only 19 residues. EL has substantial phospholipase activity, but less triglyceride lipase activity. Overexpression of EL in mice reduced plasma concentrations of HDL cholesterol and its major protein apolipoprotein A-I. The endothelial expression, enzymatic profile and in vivo effects of EL suggest that it may have a role in lipoprotein metabolism and vascular biology.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Human TG lipase family.
Figure 2: Expression of human EL.
Figure 3: Expression of EL in mice reduced HDL cholesterol and apoA-I levels.
Figure 4: Injection of AdhEL in LDL receptor-deficient mice reduced HDL cholesterol levels (a) to a greater extent than VLDL/LDL cholesterol levels ( b).


  1. 1

    Gordon, D.J. & Rifkind, B.M. High-density lipoproteins—the clinical implications of recent studies. N. Engl. J. Med. 321, 1311–1316 (1989).

  2. 2

    Breslow, J.L. Familial disorders of high density lipoprotein metabolism. in The Metabolic Basis of Inherited Disease (eds Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D.) 2031–2052 (McGraw-Hill, New York, 1995).

  3. 3

    Heller, D.A., de Faire, U., Pedersen, N.L., Dahlen, G. & McClearn, G.E. Genetic and environmental influences on serum lipid levels in twins. N. Engl. J. Med. 328 , 1150–1156 (1993).

  4. 4

    Murthy, V., Julien, P. & Gagne, C. Molecular pathobiology of the human lipoprotein lipase gene. Pharmacol. Ther. 70, 101– 135 (1996).

  5. 5

    Goldberg, J.I. Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J. Lipid Res. 37, 693 –707 (1996).

  6. 6

    Bensadoun, A. & Berryman, D.E. Genetics and molecular biology of hepatic lipase. Curr. Opin. Lipidol. 7, 77–81 (1996).

  7. 7

    Cohen, J.C., Wang, Z., Grundy, S.M., Stoesz, M.R. & Guerra, R. Variation at the hepatic lipase and apolopoprotein AI/CII/AIV loci is a major cause of genetically determined variation in plasma HDL cholesterol levels. J. Clin. Invest. 94, 2377– 2384 (1994).

  8. 8

    Guerra, R., Wang, J., Grundy, M.S. & Cohen, C.J. A hepatic lipase (LIPC) allele associated with high plasma concentrations of high density lioporotein cholesterol. Proc. Natl Acad. Sci. USA 94, 4532–4537 (1997).

  9. 9

    Winkler, F.K., D'Arcy, A. & Hunziker, W. Structure of human pancreatic lipase. Nature 343, 771–774 ( 1990).

  10. 10

    van Tilbeurgh, H., Roussel, A., Lalouel, J.M. & Cambillau, C. Lipoprotein lipase. Molecular model based on the pancreatic lipase x-ray structure: consequences for heparin binding and catalysis. J. Biol. Chem. 269, 4626–4633 ( 1994).

  11. 11

    Dugi, K.A., Dichek, H.L. & Santamarina-Fojo, S. Human hepatic and lipoprotein lipase: the loop covering the catalytic site mediates lipase substrate specificity. J. Biol. Chem. 270, 25396–25401 ( 1995).

  12. 12

    Shimada, M. et al. Overexpression of human lipoprotein lipase in transgenic mice: resistance to diet-induced hypertriglyceridemia and hypercholesterolemia. J. Biol. Chem. 268, 17924– 17929 (1993).

  13. 13

    Shimada, M. et al. Suppression of diet-induced atherosclerosis in low density lipoprotein receptor knockout mice overexpressing lipoprotein lipase. Proc. Natl Acad. Sci. USA 93, 7242– 7246 (1996).

  14. 14

    Hokanson, J.E. Lipoprotein lipase gene variants and risk of coronary disease: a quantitative analysis of population-based studies. Int. J. Clin. Lab. Res. 27, 24–34 (1997).

  15. 15

    Pimstone, N.S. et al. Mutations in the gene for lipoprotein lipase: a cause for low HDL cholesterol levels in individuals heterozygous for familial hyper-cholesterolemia. Arterioscler. Thromb. Vasc. Biol. 15, 1704 –1712 (1995).

  16. 16

    Hegele, R. et al. Hepatic lipase deficiency: clinical, biochemical, and molecular genetic characteristics. Arterioscler. Thromb. 13, 720–728 (1993).

  17. 17

    Homanics, G.E. et al. Mild dyslipidemia in mice following targeted inactivation of the hepatic lipase gene. J. Biol. Chem. 270, 2974–2980 (1995).

  18. 18

    Mezdour, H., Jones, R., Dengremont, C., Castro, G. & Maeda, N. Hepatic lipase deficiency increases plasma cholesterol but reduces susceptibility to atherosclerosis in apoliprotein E-deficient mice. J. Biol. Chem. 272, 13570 –13575 (1997).

  19. 19

    Busch, S.J. et al. Human hepatic triglyceride lipase expression reduces high density lipoprotein and aortic cholesterol in cholesterol-fed transgenic mice. J. Biol. Chem. 269, 16376– 16382 (1994).

  20. 20

    Fan, J. et al. Overexpression of hepatic lipase in transgenic rabbits leads to a marked reduction of plasma high density lipoproteins and intermediate density lipoproteins. Proc. Natl Acad. Sci. USA 91, 8724–8728 (1994).

  21. 21

    Blades, B., Vega, G.L. & Grundy, S.M. Activities of lipoprotein lipase and hepatic triacylglyceride lipase in postheparin plasma of patients with low concentrations of HDL cholesterol. Arterioscler. Thromb. 13, 1227– 1235 (1993).

  22. 22

    Mahaney, C.M. et al. A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio family heart study. Arterioscler. Thromb. Vasc. Biol. 15, 1730–1739 (1995).

  23. 23

    Kozarsky, K.F. et al. Overexpression of the HDL receptor SR-BI alters plasma HDL and bile cholesterol levels. Nature 387, 414–417 (1997).

  24. 24

    Mahley, R.W. & Zhong-Sheng, J. Remnant lipoprotein metabolism: key pathways involving cell-surface heparan sulfate proteoglycans and apolipoprotein E. J. Lipid Res. 40, 1– 16 (1999).

  25. 25

    Farese, R.V. & Herz, J. Cholesterol metabolism and embryogenesis. Trends Genet. 14, 115– 120 (1998).

  26. 26

    Tsukamoto, K., Smith, P., Glick, J.M. & Rader, D.J. Liver-directed gene transfer and prolonged expression of three major human apoE isoforms in apoE deficient mice. J. Clin. Invest. 100, 107–114 (1997).

  27. 27

    Tsukamoto, K. et al. Comparison of human apoA-I expression in mouse models of atherosclerosis after gene transfer using a second generation adenovirus. J. Lipid Res. 38, 1869–1876 ( 1997).

Download references


We thank B. Tocque, A. Minnich and J. Glick for helpful discussions and S. French, J. Bruno, R. Howk, M. McCoy, P. Smith, A. Lillethun and R. Hughes for technical assistance.

Author information

Correspondence to Daniel J. Rader.

Rights and permissions

Reprints and Permissions

About this article

Further reading