Regulation of LPL in patients with the metabolic syndrome

Recently, elevated plasma triglycerides (TG) have been shown to be an
independent risk factor for cardiovascular disease (CVD). However the etiology
of hypertriglyceridemia is complex and poorly understood. It is well known that
lipoprotein lipase (LPL) plays a crucial role in hydrolysis of
triglyceride-rich lipoproteins. More recently a new endothelial cell protein,
glycosylphosphatidylinositol-anchored high density lipoprotein*binding protein
1 (GPIHBP1) has been identified as a platform for LPL binding at the
endothelial cell surface. LPL action requires GPIHBP1 but is also modulated by
several plasma proteins including ApoCII, ApoCIII, ApoAV and ANGPTL4. To date,
the interaction between these proteins and GPIHBP1 and LPL in humans is largely
unknown.
Hypertriglyceridemia is a common feature in patients with the metabolic
syndrome (MetS) but the underlying mechanism is not completely understood. We
propose that impaired LPL action is contributing significantly to the
hypertriglyceridemic state often observed in patients with MetS.
In the current study we aim to improve our understanding of how LPL action is
impaired in these patients. We will study tissue concentrations of LPL and
GPIHBP1 and release kinetics of LPL in patients with the Mets. LPL resides in
different compartments which may affect the time span of LPL release. LPL,
bound to GPIHBP1 at the endothelial cell surface will be directly involved in
TG hydrolysis and will be quickly released after a heparin bolus. We are also
interested in testing that LPL localized in the subendothelial space will not
be readily available for lipolysis and will have slower release kinetics in
patients with MetS as it was found in a patient with GPIHBP1 deficiency. Thus a
heparin-induced LPL release curve will reflect GPIHBP1 function and will
provide valuable information on LPL action in vivo. We hope that detailed
insights into the molecular mechanisms involved in LPL action may reveal novel
targets for future treatment therapy focused on increasing LPL action and thus
improving TG homeostasis and reduce CVD risk.n the current study we aim to test
the hypothesis that LPL function is impaired in patients with the metabolic
syndrome compared to healthy controls.

1) To asses heparin-induced LPL release curves in patients with the Mets
2) To determine differences in gene expression of LPL, GPIHB1 and ANGPTL4 in
muscle and adipose tissue of patients with the MetS compared to health controls
3) To determine differences in expression of LPL, GPIHB1 and ANGPTL4 in muscle
and adipose tissue of patients with the MetS compared to health controls

This study will be a cross-sectional, case-control study

Patients and controls will visit the AMC in Amsterdam on 2 separate occasions
for a time period of 30 minutes and 2 hours respectively. Subjects should fast
overnight prior to both visits. During the screenings visit 12 millilitres of
blood will be drawn of which no side effects are to be expected. Patients on
lipid lowering drugs will be asked to discontinue treatment 4 weeks prior to
the study visit. Discontinuation of lipid lowering medication for 4 weeks in
these patients is not expected to increase risk for CVD substantially.
A fat and muscle biopsy will be performed. The risks of these procedures are
overall minimal. There can be some mild discomfort or pressure during the
needle insertion and afterwards the area may feel tender or bruised. There is a
slight risk of infection and there is also a minor risk of bruising or slight
bleeding for several days. In our experience, fat and muscle biopsy are overall
well tolerated and leave if any, minimal scarring.
During the heparin LPL test a drip will be placed which carries the risk of
developing hematoma and pain. Theoretically administration of heparin carries
the risk of bleeding, including the formation of hematoma at the place of
injection, thrombocytopenia, reversible hair loss, collapse and vascular
cramps. Since we administer 50 Units/kg we do not expect any complications. In
fact, the heparin-LPL test has been performed in our hospital for more than 5
years. We have not witnessed any adverse event following a single heparin
bolus. Due to the rapid half life of heparin, all anticoagulant effect will
have disappeared within 2 hours following heparin administration.
During the study visit blood will be drawn for the assessment of lipids,
glucose, insulin, adiponectin, ANGPTL4, apoC-III, apoA-V and LPL activity and
mass and additional blood will be drawn for storage. Since the total volume of
blood withdrawn during the study visit is less than 100 ml, no side effects are
to be expected.