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 triglycerides in lipoproteins, such as
those found in chylomicrons and very low-density lipoproteins, 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
the protein glycosylphosphatidylinositol HDL-binding protein 1 and by heparin
sulfated proteoglycans. 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 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. 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
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.
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, a lid region,
as well as a β5 loop. 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 SerHis 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. 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.
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 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 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. Pathology
Lipoprotein lipase deficiency leads to hypertriglyceridemia. 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.
Interactions 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
The LPL gene is highly conserved across vertebrates. Lipoprotein lipase is
involved in lipid transport in the placentae of live bearing lizards.
Interactive pathway map Click on genes, proteins and metabolites
below to link to respective articles. References
Further reading External links
GeneReviewsNIH/UW entry on Familial Lipoprotein Lipase Deficiency
Gene therapy for lipoprotein lipase deficiency
Lipoprotein lipase at the US National Library of Medicine Medical Subject
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