Lipoprotein Lipase an overview

particles [200,201]. Through these actions, LPL
exerts antiatherogenic effects. Of note,
subendothelially located LPL has proatherogenic
effect that increases oxidative susceptibility of LDL,
facilitating the uptake of TRL by macrophages [202].
The latter promotes foam cell formation, a hallmark
of atherogenesis [203].
In view of these heterogeneous effects, the exact
role of LPL in atherogenesis is still a matter of
debate [204]. The delicate balance between pro-
and antiatherogenic LPL appears dependent on its
location [205]. Development of gene therapy is
likely for LPL-deficient patients for a number of
reasons [206]. These patients currently lack
effective pharmacologic agents. Diagnosis of
genetic LPL deficiency can be accurately made. The
LPL gene is rather small, which allows its
incorporation into a wide range of viral vectors.
Animal models are available (LPL “knock-out” mice
and LPL-deficient kittens). LPL is naturally produced
in skeletal muscle. This tissue is easily reached via
intramuscular injection and can be targeted with
vectors with a natural tropism for this skeletal
muscle. Most patients present with detectable but
inactive LPL in the circulation. This strongly
diminishes risk of a significant immune response
against the transgenic LPL. Finally, increased LPL
activity in the human circulation was only
associated with beneficial effects. Not only does
increased LPL activity result in significant lowering
of both fasted and postprandial TG, but also it likely
increased antiatherogenic HDL cholesterol.
Effectiveness of LPL gene therapy using adenovirus
has long been established in animal models of
marked chylomicronemia and hypertriglyceridemia
[207]. Since the duration of transgene expression
upon adenoviral infection is limited, the
nonpathologic adeno-associated virus (AAV) has
been used in several gene therapy studies in males
[208]. As a transgene, the naturally occurring LPL
variant (LPLS447X) was shown to exhibit a
beneficial effect on lipid profile with a concomitant
decrease in CVD risk [209–215].
Nierman et al. [216] reported the successful
implementation of LPL gene therapy using an
AAV1-LPLS447X vector in murine and feline models
of LPL deficiency. They demonstrated that cultured
myocytes of LPL-deficient patients were able to
produce and secrete catalytically active LPL. These
promising results led to the first proposed human
LPL gene therapy trial in the Netherlands. Awaiting
its initiation, the first six LPL-deficient patients
with chylomicronemia have been thoroughly
investigated [216].
All patients were characterized by TG > 10 mmol/L
despite compliance with dietary restriction. In
addition, all patients suffered from recurrent
pancreatitis. The patients showed complete loss of
enzymatic LPL activity, whereas circulating inactive
LPL protein could be demonstrated in all (19–103%
of normal). Other patient populations that may
benefit from LPL gene therapy include heterozygote
LPL-deficient patients with the clinical phenotype
of the chylomicronemia syndrome, patients with
therapy-resistant hypertriglyceridaemia and
patients with hypertriglyceridaemia formerly
characterized as (Fredrickson) type V
hyperlipidemia. After administration of alipogene
tiparvovec, the TG content of the CM fraction and
the CM-TG/total plasma TG ratio were reduced
throughout the postprandial period. The
postprandial peak CM H level and CM H area
under the curve were greatly reduced (79% and
93%, 6 and 24 h after the test meal, respectively).
There were no significant changes in plasma NEFA
and glycerol appearance rates. Plasma glucose,
insulin, and C-peptide also did not change.
Intramuscular administration of alipogene
tiparvovec resulted in a significant improvement of
postprandial CM metabolism in LPLD patients
without inducing large postprandial NEFA spillover.
Intramuscular administration of AAV1-LPLS447X
was generally well tolerated and was associated
with reduction in overall pancreatitis incidence and
clinical improvement up to 2 years after
administration.
In summary, the results of interventional studies
suggested that markers of postprandial metabolism
such as apoB-48 could be more accurate than fasted
plasma TG to monitor the effect of AAV1-LPLS447X.
The overall benefit-risk ratio of AAV1-LPLS447X
gene therapy appears positive to date, particularly
for those with the highest risk of complications
[217,218].
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Lipids and disorders of
lipoprotein metabolism
Graham R. Bayly, in
Clinical Biochemistry: Metabolic and Clinical Aspects
(Third Edition)
, 2014
Lipoprotein lipase
Lipoprotein lipase (LPL) is an extracellular enzyme
that is bound by the glycosaminoglycan heparan
sulphate to capillary endothelial cells. It is present
in large amounts in the capillaries of adipose tissue
and muscle, both skeletal and cardiac. Lipoprotein
lipase belongs to the triglyceride lipase gene family,
which also includes HL, EL, and pancreatic
triglyceride lipase (PTL). It is the major lipolytic
enzyme involved in the intravascular metabolism of
the triglyceride-rich lipoproteins. Myocytes and
adipocytes secrete LPL in a catalytically inactive
form, which is then transported to the capillary
endothelial surface.
Along with HL and EL, LPL is a homodimer.
Interaction of the dimer with heparan sulphate on
the endothelial surface serves to anchor and
stabilize the LPL. LPL monomers that are
catalytically inactive are found in the circulation in
association with remnant particles and may play a
role in enhancing their clearance. Presence of apo
C-II is required for full activity.
Lipoprotein lipase catalyses the partial hydrolysis of
the core triglycerides of chylomicrons and VLDL to
monoglycerides and fatty acids. The fatty acids are
taken up by the tissue and either re-esterified and
stored (in adipose tissue), utilized as an energy
source (in muscle) or secreted (in lactating breast
tissue). The monoglycerides are further hydrolysed
to glycerol and fatty acids.
Lipoprotein lipase binds to heparin, which results in
its release into the circulation. This is used in the
assay of LPL activity (post-heparin lipolytic activity,
PHLA). Lipoprotein lipase regulates the plasma
concentrations of triglycerides and HDL. Individuals
with low PHLA, such as those who are heterozygous
for LPL deficiency, have high triglyceride and low
HDL concentrations in plasma, and an increased
risk of atherosclerosis.
A large number of mutations in the LPL gene have
been described. Some are a cause of the familial
chylomicronaemia syndrome (see p. 725), while
others have less severe effects. It is estimated that
20% of patients with hypertriglyceridaemia are
carriers of LPL gene mutations. The Asn291Ser
mutation is present in 2–5% of Caucasians and is
associated with a 31% increase in plasma
triglyceride concentrations and an increased risk of
coronary heart disease and type 2 diabetes. Asn291
is located in part of the molecule involved in
homodimer formation, so it is likely that this
mutation causes an increase in the relative amount
of LPL present as inactive monomer. The risk of
Alzheimer disease is also increased in Asn291Ser
carriers.
Small amounts of LPL have been demonstrated to
be present on arterial endothelium and also within
the intima of arteries. LDL binds to LPL with an
affinity similar to chylomicrons and VLDL. Although
LDL is not the physiological substrate for LPL, the
LPL present in the arterial wall may, by binding to
LDL, increase the residence time of LDL in the
arterial wall, thus promoting atherogenesis.
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Milk enzymes
Pranali Nikam, ... Suvartan Ranvir, in
Enzymes Beyond Traditional Applications in Dairy
Science and Technology
, 2023
1.4.2 Lipoprotein lipase (EC 3.1.1.34)
LPL is a 90-kDa homodimer wherein each monomer
contains 450 amino acid and 8% carbohydrates. The
enzyme mainly originates from the vascular
endothelial surfaces bounded with heparin sulfate
chains playing an important role in lipid synthesis
in the mammary gland. The optimum pH and
temperature for LPL are 9.0 and 37°C. The catalytic
activity kcat of LPL is ≈3000/s under optimum
conditions and milk has adequate lipase (1–2 mg/L;
10–20 nM) to cause hydrolytic rancidity in short
period, that is, within 10 s. However, LPL causes
hydrolytic rancidity in most of the milk samples
only if the MFGM is damaged, for example, by
agitation, foaming, cooling/warming, freezing, or
homogenization. But, some bovine milk samples
undergo spontaneous lipolysis, with no activation
step. Such milk sample contains high level of
apolipoprotein C-II, which activates LPL. Normal
milk has a higher level of proteose peptone-8 (PP-
8), which mainly inhibits LPL (Fox et al., 2015;
Girardet et al., 1993; He et al., 2012).
Caprine milk contains only ~4 % as much lipolytic
activity compared to bovine milk, but still very
prone to spontaneous rancidity and responsible for
“goaty” flavor which may be due to minor
branched-chain fatty acids, 4-methyl and 4-
ethyloctanoic acids (DeFeo et al., 1982). This
difference may due to the distribution pattern of
LPL; in bovine milk, 80% of LPL is with casein
micelles while in caprine milk only <10% of the LPL
is associated with the micelles. Ovine milk has 10%
of the LPL activity to that of bovine milk. Guinea pig
milk contains high LPL activity but rat milk has low
activity (Hamosh & Scow, 1971).
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Lipoprotein Disorders
Sekar Kathiresan, Daniel J. Rader, in
Genomic and Personalized Medicine (Second Edition)
,
2013
GPIHBP1 Deficiency
Lipoprotein lipase is synthesized by adipocytes and
cardiac and skeletal myocytes, but requires active
transport across the endothelial barrier to its site of
action on the capillary luminal surface. The mouse
knockout of the GPI-anchored protein HDL binding
protein (GPIHBP1) unexpectedly revealed marked
hypertriglyceridemia due to functional deficiency of
LPL activity (Beigneux et al., 2007). Subsequently,
mutations in GPIHBP1 in humans were found in
association with hyperchylomicronemia (Beigneux
et al., 2009a; Wang and Hegele, 2007). Biochemical
and physiological studies have demonstrated that
GPIHBP1 serves as a chaperone for LPL from its site
of synthesis to the endothelial surface, and helps to
dock LPL to the endothelium (Beigneux et al.,
2009b).
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ENZYMES INDIGENOUS TO MILK |
Lipases and Esterases
Shakeel-ur-Rehman, N.Y. Farkye, in
Encyclopedia of Dairy Sciences
, 2002
Reactions Catalysed by LPL
LPL, being a nonspecific esterase/lipase, liberates
fatty acids from the 1,3-positions in tri-, di- and
monoglycerides, and from the 1-position in
glycerophospholipids. In milk triglycerides, long
chain fatty acids are attached to glycerol at the sn-1
and sn-2 positions, while shorter chain fatty acids
are attached at the sn-3 position (Figure 1). LPL
does not hydrolyse cholesterol esters or
sphingolipid at a significant rate.
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Figure 1. The basic structure of triacylglycerol, showing positions