Lipoprotein lipase

Lipoprotein lipase
Identifiers
Symbols	LPL; HDLCQ11; LIPD
External IDs	OMIM: 609708 MGI: 96820 HomoloGene: 200 ChEMBL: 2060 GeneCards: LPL Gene
EC number	3.1.1.34
Gene Ontology Molecular function • lipoprotein lipase activity • phospholipase activity • triglyceride lipase activity • receptor binding • protein binding • heparin binding • triglyceride binding • apolipoprotein binding Cellular component • extracellular region • extracellular space • plasma membrane • cell surface • extracellular matrix • anchored to membrane • very-low-density lipoprotein particle • chylomicron Biological process • retinoid metabolic process • lipid metabolic process • fatty acid biosynthetic process • triglyceride metabolic process • phospholipid metabolic process • phototransduction, visible light • positive regulation of macrophage derived foam cell differentiation • positive regulation of cholesterol storage • positive regulation of sequestering of triglyceride • triglyceride biosynthetic process • triglyceride catabolic process • chylomicron remodeling • very-low-density lipoprotein particle remodeling • lipoprotein metabolic process • response to drug • small molecule metabolic process • triglyceride homeostasis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	4023	16956
Ensembl	ENSG00000175445	ENSMUSG00000015568
UniProt	P06858	P11152
RefSeq (mRNA)	NM_000237	NM_008509
RefSeq (protein)	NP_000228	NP_032535
Location (UCSC)	Chr 8: 19.76 – 19.82 Mb	Chr 8: 68.88 – 68.91 Mb
PubMed search
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Lipoprotein lipase (LPL) (EC 3.1.1.34) 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. It is most widely distributed in adipose, heart, and skeletal muscle tissue, as well as in lactating mammary glands.^[6][7][8]

Synthesis

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, however, the mechanism by which LPL travels across endothelial cells is still unknown.^[1][8]

Structure

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][13] 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.

Mechanism

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.^[14] The C-terminal domain is also important for binding to LDL’s receptors.^[15] 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.^[16]

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.^[13] 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]

Function

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.^[17]

Regulation

LPL is controlled transcriptionally and posttranscriptionally.^[18] The circadian clock may be important in the control of Lpl mRNA levels in peripheral tissues.^[19]

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.^[20] 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 or insulin sensitivity, or on fasting LPL activity in either tissue.^[21]

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.^[8][22] The typical concentration of LPL in plasma is in the nanomolar range.^[15]

Pathology

Lipoprotein lipase deficiency leads to hypertriglyceridemia (elevated levels of triglycerides in the bloodstream).^[23] In mice, overexpression of LPL has been shown to affect insulin response^[24][25] and to promote obesity.^[19]

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.^[26]

Interactions

Lipoprotein lipase has been shown to interact with LRP1.^[27][28][29] It is also a ligand for α2M, GP330, and VLDL receptors.^[15] 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.^[15] 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).^[30]

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". 

References

Further reading

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)