Lipoprotein lipase (LPL) (EC 3.1.1.34, systematic name triacylglycerol acylhydrolase (lipoprotein-dependent)) is a member of the
lipase
Lipase ( ) is a family of enzymes that catalyzes the hydrolysis of fats. Some lipases display broad substrate scope including esters of cholesterol, phospholipids, and of lipid-soluble vitamins and sphingomyelinases; however, these are usually tr ...
gene family, which includes
pancreatic lipase,
hepatic lipase, and
endothelial lipase. It is a water-soluble
enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different molecule ...
that
hydrolyzes
triglycerides in
lipoproteins, such as those found in
chylomicrons and
very low-density lipoproteins (VLDL), into two free
fatty acid
In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, ...
s and one
monoacylglycerol molecule:
:
triacylglycerol + H
2O = diacylglycerol + a carboxylate
It is also involved in promoting the cellular uptake of
chylomicron remnants, cholesterol-rich lipoproteins, and free fatty acids.
LPL requires
ApoC-II
Apolipoprotein C-II (Apo-CII, or Apoc-II), or apolipoprotein C2 is a protein that in humans is encoded by the gene.
The protein encoded by this gene is secreted in plasma where it is a component of very low density lipoproteins and chylomicrons ...
as a cofactor.
LPL is attached to the luminal surface of
endothelial cells in
capillaries
A capillary is a small blood vessel from 5 to 10 micrometres (μm) in diameter. Capillaries are composed of only the tunica intima, consisting of a thin wall of simple squamous endothelial cells. They are the smallest blood vessels in the body: ...
by the protein glycosylphosphatidylinositol HDL-binding protein 1 (GPIHBP1) and by heparan sulfated peptidoglycans. It is most widely distributed in adipose, heart, and
skeletal muscle
Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of m ...
tissue, as well as in lactating mammary glands.
Synthesis
In brief, LPL is secreted from heart, muscle and adipose
parenchymal cells as a
glycosylated homodimer, after which it is translocated through the
extracellular matrix
In biology, the extracellular matrix (ECM), also called intercellular matrix, is a three-dimensional network consisting of extracellular macromolecules and minerals, such as collagen, enzymes, glycoproteins and hydroxyapatite that provide struc ...
and across endothelial cells to the capillary lumen. After translation, the newly synthesized protein is glycosylated in the
endoplasmic reticulum
The endoplasmic reticulum (ER) is, in essence, the transportation system of the eukaryotic cell, and has many other important functions such as protein folding. It is a type of organelle made up of two subunits – rough 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 Golgi apparatus (), also known as the Golgi complex, Golgi body, or simply the Golgi, is an organelle found in most eukaryotic cells. Part of the endomembrane system in the cytoplasm, it packages proteins into membrane-bound vesicles ...
, the
oligosaccharides
An oligosaccharide (/ˌɑlɪgoʊˈsækəˌɹaɪd/; from the Greek ὀλίγος ''olígos'', "a few", and σάκχαρ ''sácchar'', "sugar") is a saccharide polymer containing a small number (typically two to ten) of monosaccharides (simple sug ...
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, LPL is carried across endothelial cells and presented into the capillary lumen by the protein
glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1.
Structure
Crystal structure
In crystallography, crystal structure is a description of the ordered arrangement of atoms, ions or molecules in a crystalline material. Ordered structures occur from the intrinsic nature of the constituent particles to form symmetric patterns t ...
s of LPL complexed with GPIHBP1 have been reported.
[; ][; ] LPL is composed of two distinct regions: the larger
N-terminus
The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the ami ...
domain that contains the lipolytic
active site, and the smaller
C-terminus
The C-terminus (also known as the carboxyl-terminus, carboxy-terminus, C-terminal tail, C-terminal end, or COOH-terminus) is the end of an amino acid chain (protein or polypeptide), terminated by a free carboxyl group (-COOH). When the protein i ...
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
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 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
Glycerol (), also called glycerine in British English and glycerin in American English, is a simple triol compound. It is a colorless, odorless, viscous liquid that is sweet-tasting and non-toxic. The glycerol backbone is found in lipids know ...
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.
Function
LPL gene encodes lipoprotein lipase, which is expressed 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
IDL may refer to:
Computing
* Interface description language, any computer language used to describe a software component's interface
** IDL specification language, the original IDL created by Lamb, Wulf and Nestor at Queen's University, Canada
...
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 is controlled transcriptionally and posttranscriptionally.
The
circadian clock may be important in the control of ''Lpl'' mRNA levels in peripheral tissues.
LPL
isozymes are regulated differently depending on the tissue. For example,
insulin
Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabol ...
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 insulin sensitivity or 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 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.
An ANGPTL3-4-8 model was proposed to explain the variations of LPL activity during the fed-fast cycle.
Specifically, feeding induces ANGPTL8, activating the ANGPTL8–ANGPTL3 pathway, which inhibits LPL in cardiac and skeletal muscles, thereby making circulating triglycerides available for uptake by white adipose tissue, in which LPL activity is elevated owing to diminished ANGPTL4; the reverse is true during fasting, which suppresses ANGPTL8 but induces ANGPTL4, thereby directing triglycerides to muscles. The model suggests a general framework for how triglyceride trafficking is regulated.
Clinical significance
Lipoprotein lipase deficiency leads to
hypertriglyceridemia (elevated levels of
triglycerides in the bloodstream).
In mice, overexpression of LPL has been shown to cause
insulin resistance
Insulin resistance (IR) is a pathological condition in which cells fail to respond normally to the hormone insulin.
Insulin is a hormone that facilitates the transport of glucose from blood into cells, thereby reducing blood glucose (blood suga ...
,
and to promote obesity.
A high adipose 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.
LPL expression has been shown to be a prognostic predictor in
Chronic lymphocytic leukemia. In this haematological disorder, LPL appears to provide fatty acids as an energy source to malignant cells. Thus, elevated levels of LPL mRNA or protein are considered to be indicators of poor prognosis.
Interactions
Lipoprotein lipase has been shown to
interact with
LRP1.
It is also a ligand for
α2M
α2-Macroglobulin (α2M), or alpha-2-macroglobulin, is a large (720 KDa) plasma protein found in the blood. It is mainly produced by the liver, and also locally synthesized by macrophages, fibroblasts, and adrenocortical cells. In humans it i ...
,
GP330
The Offshore Racing Congress (ORC) is an international body for the sport of competitive sailing and is responsible for the establishment and maintenance of rating and classification standards used to define offshore, that is marine as opposed to ...
, 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
ApoCIII
Apolipoprotein C-III also known as apo-CIII, and apolipoprotein C3, is a protein that in humans is encoded by the ''APOC3'' gene. Apo-CIII is secreted by the liver as well as the small intestine, and is found on triglyceride-rich lipoproteins such ...
.
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'').
Interactive pathway map
References
Further reading
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External links
GeneReviews/NCBI/NIH/UW entry on Familial Lipoprotein Lipase Deficiency
Gene therapy for lipoprotein lipase deficiency*
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EC 3.1.1