Lipoprotein lipase
Encyclopedia
Lipoprotein lipase 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 triglyceride
s in lipoprotein
s, such as those found in chylomicron
s and very low-density lipoprotein
s (VLDL), into two free fatty acid
s 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 Apo-CII as a cofactor.
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.
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 is 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).
Homodimerization is required before LPL can be secreted from cells. After secretion, however, the mechanism by which LPL travels across endothelial cells is still unknown.
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.
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 Apo-CII 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 Apo-CII 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.
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.
The form that is in adipocytes is activated by insulin
, whereas that in muscle and myocardium is activated by glucagon and epinepherine. This helps to explain why during fasting, LPL activity increases in muscle tissue and decreases in adipose tissue. After feasting, the opposite occurs.
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.
leads to hypertriglyceridemia
(elevated levels of triglyceride
s in the bloodstream).
Diets high in refined carbohydrates have been shown to cause tissue-specific overexpression of LPL. This has been implicated in tissue-specific insulin resistance
and consequent development of type 2 diabetes mellitus & obesity
.
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, the 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 Apo-CII, it is inhibited by Apo-CIII.
Lipase
A lipase is an enzyme that catalyzes the formation or cleavage of fats . Lipases are a subclass of the esterases.Lipases perform essential roles in the digestion, transport and processing of dietary lipids in most, if not all, living organisms...
gene family, which includes pancreatic lipase
Pancreatic lipase
Pancreatic lipase, also known as pancreatic triacylglycerol lipase, is secreted from the pancreas, and is the primary lipase that hydrolyzes dietary fat molecules in the human digestive system, converting triglyceride substrates found in ingested oils to monoglycerides and free fatty acids.Bile...
, hepatic lipase
Hepatic lipase
Hepatic lipase is a form of lipase. It is expressed in the liver and adrenal glands.One of the principal functions of hepatic lipase is to convert IDL to LDL.-Clinical significance:...
, and endothelial lipase
Endothelial lipase
Endothelial lipase is a form of lipase secreted by the endothelial cells.It was first characterized in 1999....
. It is a water soluble enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that hydrolyzes triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s in lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...
s, such as those found in chylomicron
Chylomicron
Chylomicrons are lipoprotein particles that consist of triglycerides , phospholipids , cholesterol and proteins .They transport dietary lipids from the intestines to other locations in the body...
s and very low-density lipoprotein
Very low density lipoprotein
Very-low-density lipoprotein is a type of lipoprotein made by the liver. VLDL is one of the five major groups of lipoproteins that enable fats and cholesterol to move within the water-based solution of the bloodstream...
s (VLDL), into two free fatty acid
Fatty acid
In chemistry, especially biochemistry, a fatty acid is a carboxylic acid with a long unbranched aliphatic tail , which is either saturated or unsaturated. Most naturally occurring fatty acids have a chain of an even number of carbon atoms, from 4 to 28. Fatty acids are usually derived from...
s 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 Apo-CII as a cofactor.
LPL is attached to the luminal surface of endothelial cells
Endothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
in capillaries. It is most widely distributed in adipose, heart, and skeletal muscle tissue, as well as in lactating mammary glands.
Synthesis
In brief, LPL is secreted from parenchymal cells as a glycosylatedGlycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
homodimer, after which it is translocated through the extracellular matrix
Extracellular matrix
In biology, the extracellular matrix is the extracellular part of animal tissue that usually provides structural support to the animal cells in addition to performing various other important functions. The extracellular matrix is the defining feature of connective tissue in animals.Extracellular...
and across endothelial cells to the capillary lumen. After translation, the newly synthesized protein is glycosylated in the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
. The glycosylation sites of LPL are Asn-43, Asn-257, and Asn-359. Glucosidases
Glucosidases
Glucosidases are glycoside hydrolase enzymes categorized under the EC number 3.2.1.-Function:α-glucosidases are enzymes involved in breaking down complex carbohydrates such as starch and glycogen...
then remove terminal glucose residues; it is 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
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
, 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).
Homodimerization is required before LPL can be secreted from cells. After secretion, however, the mechanism by which LPL travels across endothelial cells is still unknown.
Structure
The crystal structureCrystal structure
In mineralogy and crystallography, crystal structure is a unique arrangement of atoms or molecules in a crystalline liquid or solid. A crystal structure is composed of a pattern, a set of atoms arranged in a particular way, and a lattice exhibiting long-range order and symmetry...
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
Active site
In biology the active site is part of an enzyme where substrates bind and undergo a chemical reaction. The majority of enzymes are proteins but RNA enzymes called ribozymes also exist. The active site of an enzyme is usually found in a cleft or pocket that is lined by amino acid residues that...
, 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
Alpha/beta hydrolase fold
In molecular biology, the alpha/beta hydrolase fold is common to a number of hydrolytic enzymes of widely differing phylogenetic origin and catalytic function. The core of each enzyme is an alpha/beta-sheet , containing 8 strands connected byhelices...
, which is a globular structure containing a central β sheet
Beta sheet
The β sheet is the second form of regular secondary structure in proteins, only somewhat less common than the alpha helix. Beta sheets consist of beta strands connected laterally by at least two or three backbone hydrogen bonds, forming a generally twisted, pleated sheet...
surrounded by α helices
Alpha helix
A common motif in the secondary structure of proteins, the alpha helix is a right-handed coiled or spiral conformation, in which every backbone N-H group donates a hydrogen bond to the backbone C=O group of the amino acid four residues earlier...
. The C-terminus domain is a β sandwich formed by two β sheet layers, and resembles an elongated cylinder.
Mechanism
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 Apo-CII 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 heparinHeparin
Heparin , also known as unfractionated heparin, a highly sulfated glycosaminoglycan, is widely used as an injectable anticoagulant, and has the highest negative charge density of any known biological molecule...
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 Apo-CII 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
Glycerol
Glycerol is a simple polyol compound. It is a colorless, odorless, viscous liquid that is widely used in pharmaceutical formulations. Glycerol has three hydroxyl groups that are responsible for its solubility in water and its hygroscopic nature. The glycerol backbone is central to all lipids...
backbone of the lipid is then able to enter the active site and is hydrolyzed.
Two molecules of Apo-CII 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.
Function
LPL encodes lipoprotein lipase, which is expressed in 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.Regulation
LPL isozymes are regulated differently depending on the tissue. For example, insulinInsulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
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.
The form that is in adipocytes is activated by insulin
Insulin
Insulin is a hormone central to regulating carbohydrate and fat metabolism in the body. Insulin causes cells in the liver, muscle, and fat tissue to take up glucose from the blood, storing it as glycogen in the liver and muscle....
, whereas that in muscle and myocardium is activated by glucagon and epinepherine. This helps to explain why during fasting, LPL activity increases in muscle tissue and decreases in adipose tissue. After feasting, the opposite occurs.
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.
Pathology
Lipoprotein lipase deficiencyLipoprotein lipase deficiency
Lipoprotein lipase deficiency is caused by a mutation in the gene which codes lipoprotein lipase....
leads to hypertriglyceridemia
Hypertriglyceridemia
In medicine, hypertriglyceridemia denotes high blood levels of triglycerides, the most abundant fatty molecule in most organisms. It has been associated with atherosclerosis, even in the absence of hypercholesterolemia . It can also lead to pancreatitis in excessive concentrations In medicine,...
(elevated levels of triglyceride
Triglyceride
A triglyceride is an ester derived from glycerol and three fatty acids. There are many triglycerides, depending on the oil source, some are highly unsaturated, some less so....
s in the bloodstream).
Diets high in refined carbohydrates have been shown to cause tissue-specific overexpression of LPL. This has been implicated in tissue-specific insulin resistance
Insulin resistance
Insulin resistance is a physiological condition where the natural hormone insulin becomes less effective at lowering blood sugars. The resulting increase in blood glucose may raise levels outside the normal range and cause adverse health effects, depending on dietary conditions. Certain cell types...
and consequent development of type 2 diabetes mellitus & obesity
Obesity
Obesity is a medical condition in which excess body fat has accumulated to the extent that it may have an adverse effect on health, leading to reduced life expectancy and/or increased health problems...
.
Interactions
Lipoprotein lipase has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with LRP1
LRP1
Low density lipoprotein receptor-related protein 1 , also known as alpha-2-macroglobulin receptor , apolipoprotein E receptor or cluster of differentiation 91 , is a protein forming a receptor found in the plasma membrane of cells involved in receptor-mediated endocytosis...
. It is also a ligand for α2M, GP330, and VLDL receptors. LPL has been shown to be a ligand for LRP2
LRP2
Low density lipoprotein-related protein 2 also known as LRP2 or megalin is a protein which in humans is encoded by the LRP2 gene.-Function:...
, albeit at a lower affinity than for other receptors; however, the 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 Apo-CII, it is inhibited by Apo-CIII.