Lipoprotein lipase (LPL) is an enzyme that plays an important role in removing triglycerides (TG) (molecules that transport dietary fat) from the blood. Patients with LPL deficiency (LPLD) display during their whole life very high plasma TG levels often associated with episodes of postprandial abdominal pain, malaise, blurred vision, dizziness (hyperchylomicronemia syndrome) that may lead to recurrent pancreatitis episodes. Because of their very slow clearance in blood of their chylomicron-TG, these patients need to severely restrict their dietary fat intake to avoid these complications. Fortunately, novel treatments are being developed to circumvent LPL deficiency (LPLD) metabolic effect on chylomicron-TG clearance. However, there is no data on how LPLD affect organ-specific dietary fatty acid metabolism nor how the novel therapeutic agents may change this metabolism. For example, it is currently not understood how subjects with LPLD store their DFA into adipose tissues and whether they are able to use DFA as a fuel to sustain their cardiac metabolism, as healthy individuals do. This study aims to better understand theses two questions.
8 healthy LPL-deficient individuals (LPLD subjects) with history of fasting TG > 5 mmol/l and homozygote or compound heterozygote for a LPL-gene mutation;
8 control subjects (fasting glucose < 5.6, 2-hour post 75g OGTT glucose < 7.8 mmol/l and HbA1c < 5.8%; fasting TG < 1.5 mmol/l);
age 18 to 75 yo;
To be willing and able to adhere to the specifications of the protocol;
age < 18 yo;
overt cardiovascular disease as assessed by medical history, physical exam, and abnormal ECG
Treatment with a fibrate, thiazolidinedione, beta-blocker or other drug known to affect lipid or carbohydrate metabolism (except statins, metformin, and other antihypertensive agents that can be safely interrupted);
Treatment with anti-hypertensive medication (only for LPL-deficient individuals);
Parallel
Heparin
Drugan intravenous (i.v.) heparin bolus (50 IU/kg i.v.) followed by 250 IU/h i.v. during 6 hours, starting 15 minutes before ingestion of liquid meal
liquid meal
Dietary supplementlow fat meal: (500 mL, 898 Kcal, 13% fat, 20.3% protein and 62.3% carbohydrates) will be ingested over 20 minutes
Organ-specific Dietary Fatty Acid (DFA) partitioning
will be determined using oral administration of \[18F \]-Fluoro-6-Thia- Heptadecanoic Acid (FTHA ) during whole-body acquisition.
Myocardial DFA uptake
will be assessed using oral administration of \[18F\]-FTHA during dynamic PET acquisition.
Myocardial nonesterified fatty acids (NEFA) metabolism
will be determined using \[11C\]-palmitate during dynamic PET acquisition.
Dietary fatty acid oxidation rate
will be measured using breath \[13C\]-carbon dioxide enrichment
Total oxidation rate
will be determined by indirect calorimetry
postprandial plasma NEFA turnover
will be determined using stable isotope tracers of fatty acids
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Université de Sherbrooke
Lead sponsor
Institut de Recherches Cliniques de Montreal
Collaborator
