Lipoprotein lipase

Lipoprotein lipase

Lipoprotein lipase
Symbols  ; HDLCQ11; LIPD
External IDs ChEMBL: GeneCards:
EC number
RNA expression pattern
Species Human Mouse
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
PubMed search
Lipoprotein lipase
EC number
CAS number 9004-02-8
IntEnz IntEnz view
ExPASy NiceZyme view
MetaCyc metabolic pathway
PRIAM profile
PDB structures RCSB PDB PDBe PDBsum
Gene Ontology AmiGO / EGO

Lipoprotein lipase (LPL) (EC is a member of the lipase gene family, which includes pancreatic lipase, hepatic lipase, and endothelial lipase. It is a water-soluble enzyme that hydrolyzes triglycerides in lipoproteins, such as those found in chylomicrons and very low-density lipoproteins (VLDL), into two free fatty acids and one monoacylglycerol molecule. It is also involved in promoting the cellular uptake of chylomicron remnants, cholesterol-rich lipoproteins, and free fatty acids.[1][2][3] LPL requires ApoC-II as a cofactor.[4][5]

LPL is attached to the luminal surface of endothelial cells in capillaries by the protein glycosylphosphatidylinositol HDL-binding protein 1 (GPIHBP1) and by heparin sulfated proteoglycans. It is most widely distributed in adipose, heart, and skeletal muscle tissue, as well as in lactating mammary glands.[6][7][8]


  • Synthesis 1
  • Structure 2
  • Mechanism 3
  • Function 4
  • Regulation 5
  • Pathology 6
  • Interactions 7
  • In other organisms 8
  • Interactive pathway map 9
  • References 10
  • Further reading 11
  • External links 12


In brief, LPL is secreted from parenchymal cells as a glycosylated homodimer, after which it is translocated through the extracellular matrix and across endothelial cells to the capillary lumen. After translation, the newly synthesized protein is glycosylated in the endoplasmic reticulum. The glycosylation sites of LPL are Asn-43, Asn-257, and Asn-359.[1] Glucosidases then remove terminal glucose residues; it was once believed that this glucose trimming is responsible for the conformational change needed for LPL to form homodimers and become catalytically active.[1][8][9][10] In the Golgi apparatus, the oligosaccharides are further altered to result in either two complex chains, or two complex and one high-mannose chain.[1][8] In the final protein, carbohydrates account for about 12% of the molecular mass (55-58 kDa).[1][8][11]

Homodimerization is required before LPL can be secreted from cells.[11][12] After secretion, LPL is carried across endothelial cells and presented into the capillary lumen by the protein Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.[13][14]


The crystal structure of LPL has not been discovered; however, there are substantial experimental evidence and structural homology between members of the lipase family to predict the likely structure and functional regions of the enzyme.[10][15] LPL is composed of two distinct regions: the larger N-terminus domain that contains the lipolytic active site, and the smaller C-terminus domain. These two regions are attached by a peptide linker. The N-terminus domain has an α/β hydrolase fold, which is a globular structure containing a central β sheet surrounded by α helices. The C-terminus domain is a β sandwich formed by two β sheet layers, and resembles an elongated cylinder.


Image 1: The proposed LPL homodimer structure; N-terminal domains in blue, C-terminal domains in orange. Lid region blocking the active site is shown in dark blue. Triglyceride binds to the C-terminal domain and the lid region, inducing a conformation change in LPL to make the active site accessible.

The active site of LPL is composed of the conserved Ser-132, Asp-156, and His-241 triad. Other important regions of the N-terminal domain for catalysis includes an oxyanion hole (Trp-55, Leu-133), a lid region (residues 216-239), as well as a β5 loop (residues 54-64).[1][6][10] The ApoC-II binding site is currently unknown, but it is predicted that residues on both N-and C-terminal domains are necessary for this interaction to occur. The C-terminal domain appears to confer LPL’s substrate specificity; it has a higher affinity for large triacylglyceride-rich lipoproteins than cholesterol-rich lipoproteins.[16] The C-terminal domain is also important for binding to LDL’s receptors.[17] Both the N-and C-terminal domains contain heparin binding sites distal to the lipid binding sites; LPL therefore serves as a bridge between the cell surface and lipoproteins. Importantly, LPL binding to the cell surface or receptors is not dependent on its catalytic activity.[18]

The LPL non-covalent homodimer has a head-to-tail arrangement of the monomers. The Ser/Asp/His triad is contained in a hydrophobic groove that is blocked from solvent by the lid.[1][6] Upon binding to ApoC-II and lipid in the lipoprotein, the C-terminal domain presents the lipid substrate to the lid region. The lipid interacts with both the lid region and the hydrophobic groove at the active site; this causes the lid to move, providing access to the active site. The β5 loop folds back into the protein core, bringing one of the electrophiles of the oxyanion hole into position for lipolysis.[1] The glycerol backbone of the lipid is then able to enter the active site and is hydrolyzed.

Two molecules of ApoC-II can attach to each LPL dimer.[15] It is estimated that up to forty LPL dimers may act simultaneously on a single lipoprotein.[1] In regard to kinetics, it is believed that release of product into circulation is the rate-limiting step in the reaction.[6]


LPL encodes lipoprotein lipase, which is expressed on endothelial cells in the heart, muscle, and adipose tissue. LPL functions as a homodimer, and has the dual functions of triglyceride hydrolase and ligand/bridging factor for receptor-mediated lipoprotein uptake. Through catalysis, VLDL is converted to IDL and then to LDL. Severe mutations that cause LPL deficiency result in type I hyperlipoproteinemia, while less extreme mutations in LPL are linked to many disorders of lipoprotein metabolism.[19]


LPL is controlled transcriptionally and posttranscriptionally.[20] The circadian clock may be important in the control of Lpl mRNA levels in peripheral tissues.[21]

LPL isozymes are regulated differently depending on the tissue. For example, insulin is known to activate LPL in adipocytes and its placement in the capillary endothelium. By contrast, insulin has been shown to decrease expression of muscle LPL.[22] Muscle and myocardial LPL is instead activated by glucagon and adrenaline. This helps to explain why during fasting, LPL activity increases in muscle tissue and decreases in adipose tissue, whereas after a meal, the opposite occurs.[1][8]

Consistent with this, dietary macronutrients differentially affect adipose and muscle LPL activity. After 16 days on a high-carbohydrate or a high-fat diet, LPL activity increased significantly in both tissues 6 hours after a meal of either composition, but there was a significantly greater rise in adipose tissue LPL in response to the high-carbohydrate diet compared to the high-fat diet. There was no difference between the two diets' effects on insulin sensitivity or fasting LPL activity in either tissue.[23]

The concentration of LPL displayed on endothelial cell surface cannot be regulated by endothelial cells, as they neither synthesize nor degrade LPL. Instead, this regulation occurs by managing the flux of LPL arriving at the lipolytic site and by regulating the activity of LPL present on the endothelium. A key protein involved in controlling the activity of LPL is ANGPTL4, which serves as a local inhibitor of LPL. Induction of ANGPTL4 accounts for the inhibition of LPL activity in white adipose tissue during fasting. Growing evidence implicates ANGPTL4 in the physiological regulation of LPL activity in a variety of tissues.[24]


Lipoprotein lipase deficiency leads to hypertriglyceridemia (elevated levels of triglycerides in the bloodstream).[25] In mice, overexpression of LPL has been shown to affect insulin response[26][27] and to promote obesity.[21]

A high tissue LPL response to a high-carbohydrate diet may predispose toward fat gain. One study reported that subjects gained more body fat over the next four years if, after following a high-carbohydrate diet and partaking of a high-carbohydrate meal, they responded with an increase in adipose tissue LPL activity per adipocyte, or a decrease in skeletal muscle LPL activity per gram of tissue.[28]


Lipoprotein lipase has been shown to interact with LRP1.[29][30][31] It is also a ligand for α2M, GP330, and VLDL receptors.[17] LPL has been shown to be a ligand for LRP2, albeit at a lower affinity than for other receptors; however, most of the LPL-dependent VLDL degradation can be attributed to the LRP2 pathway.[17] In each case, LPL serves as a bridge between receptor and lipoprotein. While LPL is activated by ApoC-II, it is inhibited by ApoC-III.[6]

In other organisms

The LPL gene is highly conserved across vertebrates. Lipoprotein lipase is involved in lipid transport in the placentae of live bearing lizards (Pseudemoia entrecasteauxii).[32]

Interactive pathway map

Click on genes, proteins and metabolites below to link to respective articles. [§ 1]

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Statin Pathway edit
  1. ^ The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430". 


  1. ^ a b c d e f g h i j Mead JR, Irvine SA, Ramji DP (December 2002). "Lipoprotein lipase: structure, function, regulation, and role in disease". J. Mol. Med. 80 (12): 753–69.  
  2. ^ Rinninger F, Kaiser T, Mann WA, Meyer N, Greten H, Beisiegel U (July 1998). "Lipoprotein lipase mediates an increase in the selective uptake of high density lipoprotein-associated cholesteryl esters by hepatic cells in culture". J. Lipid Res. 39 (7): 1335–48.  
  3. ^ Ma Y, Henderson HE, Liu MS, Zhang H, Forsythe IJ, Clarke-Lewis I, Hayden MR, Brunzell JD (November 1994). "Mutagenesis in four candidate heparin binding regions (residues 279-282, 291-304, 390-393, and 439-448) and identification of residues affecting heparin binding of human lipoprotein lipase". J. Lipid Res. 35 (11): 2049–59.  
  4. ^ Kim SY, Park SM, Lee ST (January 2006). "Apolipoprotein C-II is a novel substrate for matrix metalloproteinases". Biochem. Biophys. Res. Commun. 339 (1): 47–54.  
  5. ^ Kinnunen PK, Jackson RL, Smith LC, Gotto AM, Sparrow JT (November 1977). "Activation of lipoprotein lipase by native and synthetic fragments of human plasma apolipoprotein C-II". Proc. Natl. Acad. Sci. U.S.A. 74 (11): 4848–51.  
  6. ^ a b c d e Wang CS, Hartsuck J, McConathy WJ (January 1992). "Structure and functional properties of lipoprotein lipase". Biochim. Biophys. Acta 1123 (1): 1–17.  
  7. ^ Wong H, Schotz MC (July 2002). "The lipase gene family". J. Lipid Res. 43 (7): 993–9.  
  8. ^ a b c d e Braun JE, Severson DL (October 1992). "Regulation of the synthesis, processing and translocation of lipoprotein lipase". Biochem. J. 287 (2): 337–47.  
  9. ^ Semb H, Olivecrona T (March 1989). "The relation between glycosylation and activity of guinea pig lipoprotein lipase". J. Biol. Chem. 264 (7): 4195–200.  
  10. ^ a b c Wong H, Davis RC, Thuren T, Goers JW, Nikazy J, Waite M, Schotz MC (April 1994). "Lipoprotein lipase domain function". J. Biol. Chem. 269 (14): 10319–23.  
  11. ^ a b Vannier C, Ailhaud G (August 1989). "Biosynthesis of lipoprotein lipase in cultured mouse adipocytes. II. Processing, subunit assembly, and intracellular transport". J. Biol. Chem. 264 (22): 13206–16.  
  12. ^ Ong JM, Kern PA (February 1989). "The role of glucose and glycosylation in the regulation of lipoprotein lipase synthesis and secretion in rat adipocytes". J. Biol. Chem. 264 (6): 3177–82.  
  13. ^ Beigneux AP, Davies BS, Gin P, Weinstein MM, Farber E, Qiao X, Peale F, Bunting S, Walzem RL, Wong JS, Blaner WS, Ding ZM, Melford K, Wongsiriroj N, Shu X, de Sauvage F, Ryan RO, Fong LG, Bensadoun A, Young SG. (2007). "Glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 plays a critical role in the lipolytic processing of chylomicrons.". Cell Metabolism 5 (4): 279–291.  
  14. ^ Davies BS, Beigneux AP, Barnes RH 2nd, Tu Y, Gin P, Weinstein MM, Nobumori C, Nyrén R, Goldberg I, Olivecrona G, Bensadoun A, Young SG, Fong LG. (2010). "GPIHBP1, an endothelial cell transporter for lipoprotein lipase.". Cell Metabolism 12 (1): 42–53.  
  15. ^ a b McIlhargey TL, Yang Y, Wong H, Hill JS (June 2003). "Identification of a lipoprotein lipase cofactor-binding site by chemical cross-linking and transfer of apolipoprotein C-II-responsive lipolysis from lipoprotein lipase to hepatic lipase". J. Biol. Chem. 278 (25): 23027–35.  
  16. ^ Lookene A, Nielsen MS, Gliemann J, Olivecrona G (April 2000). "Contribution of the carboxy-terminal domain of lipoprotein lipase to interaction with heparin and lipoproteins". Biochem. Biophys. Res. Commun. 271 (1): 15–21.  
  17. ^ a b c Medh JD, Bowen SL, Fry GL, Ruben S, Andracki M, Inoue I, Lalouel JM, Strickland DK, Chappell DA (July 1996). "Lipoprotein lipase binds to low density lipoprotein receptors and induces receptor-mediated catabolism of very low density lipoproteins in vitro". J. Biol. Chem. 271 (29): 17073–80.  
  18. ^ Beisiegel U, Weber W, Bengtsson-Olivecrona G (October 1991). "Lipoprotein lipase enhances the binding of chylomicrons to low density lipoprotein receptor-related protein". Proc. Natl. Acad. Sci. U.S.A. 88 (19): 8342–6.  
  19. ^ "Entrez Gene: LPL lipoprotein lipase". 
  20. ^ Wang H, Eckel RH (2009). "Lipoprotein lipase: from gene to obesity.". Am J Physiol Endocrinol Metab 297 (2): E271–88.  
  21. ^ a b Delezie J, Dumont S, Dardente H, Oudart H, Gréchez-Cassiau A, Klosen P, et al. (2012). "The nuclear receptor REV-ERBα is required for the daily balance of carbohydrate and lipid metabolism.". FASEB J 26 (8): 3321–35.  
  22. ^ Kiens B, Lithell H, Mikines KJ, Richter EA (October 1989). "Effects of insulin and exercise on muscle lipoprotein lipase activity in man and its relation to insulin action". J. Clin. Invest. 84 (4): 1124–9.  
  23. ^ Yost TJ, Jensen DR, Haugen BR, Eckel RH (August 1998). "Effect of dietary macronutrient composition on tissue-specific lipoprotein lipase activity and insulin action in normal-weight subjects" (PDF). Am. J. Clin. Nutr. 68 (2): 296–302.  
  24. ^ Dijk W, Kersten S. (2014). "Regulation of lipoprotein lipase by Angptl4.". Trends Endocrinol Metab. 25 (3): 146–155.  
  25. ^ Okubo M, Horinishi A, Saito M, Ebara T, Endo Y, Kaku K, Murase T, Eto M (November 2007). "A novel complex deletion-insertion mutation mediated by Alu repetitive elements leads to lipoprotein lipase deficiency". Mol. Genet. Metab. 92 (3): 229–33.  
  26. ^ Ferreira LD, Pulawa LK, Jensen DR, Eckel RH (2001). "Overexpressing human lipoprotein lipase in mouse skeletal muscle is associated with insulin resistance.". Diabetes 50 (5): 1064–8.  
  27. ^ Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, et al. (2001). "Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance.". Proc Natl Acad Sci U S A 98 (13): 7522–7.  
  28. ^ Ferland A, Château-Degat ML, Hernandez TL, Eckel RH (May 2012). "Tissue-specific responses of lipoprotein lipase to dietary macronutrient composition as a predictor of weight gain over 4 years". Obesity (Silver Spring) 20 (5): 1006–11.  
  29. ^ Williams SE, Inoue I, Tran H, Fry GL, Pladet MW, Iverius PH, Lalouel JM, Chappell DA, Strickland DK (March 1994). "The carboxyl-terminal domain of lipoprotein lipase binds to the low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor (LRP) and mediates binding of normal very low density lipoproteins to LRP". J. Biol. Chem. 269 (12): 8653–8.  
  30. ^ Nykjaer A, Nielsen M, Lookene A, Meyer N, Røigaard H, Etzerodt M, Beisiegel U, Olivecrona G, Gliemann J (December 1994). "A carboxyl-terminal fragment of lipoprotein lipase binds to the low density lipoprotein receptor-related protein and inhibits lipase-mediated uptake of lipoprotein in cells". J. Biol. Chem. 269 (50): 31747–55.  
  31. ^ Chappell DA, Fry GL, Waknitz MA, Iverius PH, Williams SE, Strickland DK (December 1992). "The low density lipoprotein receptor-related protein/alpha 2-macroglobulin receptor binds and mediates catabolism of bovine milk lipoprotein lipase". J. Biol. Chem. 267 (36): 25764–7.  
  32. ^ Griffith, O. W., Ujvari, B., Belov, K., & Thompson, M. B. (2013). Placental lipoprotein lipase (LPL) gene expression in a placentotrophic lizard, Pseudemoia entrecasteauxii. Journal of Experimental Zoology Part B: Molecular and Developmental Evolution.

Further reading

  • Zechner R (1997). "The tissue-specific expression of lipoprotein lipase: implications for energy and lipoprotein metabolism". Curr. Opin. Lipidol. 8 (2): 77–88.  
  • Fisher RM, Humphries SE, Talmud PJ (1998). "Common variation in the lipoprotein lipase gene: effects on plasma lipids and risk of atherosclerosis". Atherosclerosis 135 (2): 145–59.  
  • Beisiegel U (1998). "Lipoprotein metabolism". Eur. Heart J. 19 Suppl A: A20–3.  
  • Pentikäinen MO, Oksjoki R, Oörni K, Kovanen PT (2002). "Lipoprotein lipase in the arterial wall: linking LDL to the arterial extracellular matrix and much more". Arterioscler. Thromb. Vasc. Biol. 22 (2): 211–7.  
  • Mead JR, Irvine SA, Ramji DP (2003). "Lipoprotein lipase: structure, function, regulation, and role in disease". J. Mol. Med. 80 (12): 753–69.  
  • Lichtenstein L, Berbée JF, van Dijk SJ, van Dijk KW, Bensadoun A, Kema IP, Voshol PJ, Müller M, Rensen PC, Kersten S (November 2007). "Angptl4 upregulates cholesterol synthesis in liver via inhibition of LPL- and HL-dependent hepatic cholesterol uptake". Arterioscler. Thromb. Vasc. Biol. 27 (11): 2420–7.  
  • Lichtenstein L, Mattijssen F, de Wit NJ, Georgiadi A, Hooiveld GJ, van der Meer R, He Y, Qi L, Köster A, Tamsma JT, Tan NS, Müller M, Kersten S (December 2010). "Angptl4 protects against severe proinflammatory effects of saturated fat by inhibiting fatty acid uptake into mesenteric lymph node macrophages". Cell Metab. 12 (6): 580–92.  

External links

  • GeneReviews/NCBI/NIH/UW entry on Familial Lipoprotein Lipase Deficiency
  • Gene therapy for lipoprotein lipase deficiency
  • Lipoprotein lipase at the US National Library of Medicine Medical Subject Headings (MeSH)