|Symbols||; HDLCQ11; LIPD|
|External IDs||ChEMBL: GeneCards:|
|RNA expression pattern|
|PDB structures||RCSB PDB PDBe PDBsum|
|Gene Ontology||AmiGO / EGO|
Lipoprotein lipase (LPL) (EC 184.108.40.206) 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. LPL requires ApoC-II as a cofactor.
LPL is attached to the luminal surface of endothelial cells in capillaries by heparen sulfated proteoglycans. It is most widely distributed in adipose, heart, and skeletal muscle tissue, as well as in lactating mammary glands.
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. 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. In the Golgi apparatus, the oligosaccharides are further altered to result in either two complex chains, or two complex and one high-mannose chain. In the final protein, carbohydrates account for about 12% of the molecular mass (55-58 kDa).
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. 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.
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). 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. The C-terminal domain is also important for binding to LDL’s receptors. 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.
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. 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. 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. It is estimated that up to forty LPL dimers may act simultaneously on a single lipoprotein. In regard to kinetics, it is believed that release of product into circulation is the rate-limiting step in the reaction.
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.
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. 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.
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 or insulin sensitivity, or on fasting LPL activity in either tissue.
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 being released into circulation attached to lipoproteins. The typical concentration of LPL in plasma is in the nanomolar range.
Lipoprotein lipase deficiency leads to hypertriglyceridemia (elevated levels of triglycerides in the bloodstream). In mice, overexpression of LPL has been shown to affect insulin response and to promote obesity.
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.
Lipoprotein lipase has been shown to interact with LRP1. It is also a ligand for α2M, GP330, and VLDL receptors. 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. 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.
In other organisms
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles. [§ 1]
- The interactive pathway map can be edited at WikiPathways: "Statin_Pathway_WP430".
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- "Entrez Gene: LPL lipoprotein lipase".
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- 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. PMID 7510694.
- 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. PMID 7989348.
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- Beisiegel U (1998). "Lipoprotein metabolism". Eur. Heart J. 19 Suppl A: A20–3. PMID 9519338.
- 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. doi:10.1161/hq0102.101551. PMID 11834518.
- Mead JR, Irvine SA, Ramji DP (2003). "Lipoprotein lipase: structure, function, regulation, and role in disease". J. Mol. Med. 80 (12): 753–69. doi:10.1007/s00109-002-0384-9. PMID 12483461.
- 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. doi:10.1161/ATVBAHA.107.151894. PMID 17761937.
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- 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)