Dietary Fat and High-Density Lipoprotein (HDL) Metabolism-Effect of Carbohydrate and Fat Intake

The investigators will study the kinetics of multiple types of high-density lipoprotein
(HDL) in humans under two strictly controlled dietary conditions, high unsaturated fat and
high carbohydrate, in 20 individuals with low HDL cholesterol and overweight or obesity. The
participants will be given the controlled diets for 4 weeks in a randomized crossover
design. They will be admitted to the Brigham & Women's Hospital Center for Clinical
Investigation (CCI) the morning of Day 28 when they will be infused intravenously with a
stable isotope tracer, trideuterated (D3), leucine for 10 minutes as a bolus. Blood will be
sampled in the hospital through 24 hours, and thereafter at the ambulatory clinical center
throughout 94 hours. HDL subtypes will be prepared in Dr. Sacks's laboratory at Harvard
School of Public Health (HSPH) and analyzed for content of lipids and proteins, and for
incorporation of the tracer into apolipoprotein A-I, the principal protein of HDL. These
data will be studied by interactive modeling to a multi-compartment model of human HDL
physiology that best fits the observed data. The model will yield HDL metabolic rates during
unsaturated fat and carbohydrate-rich diets which will be tested for statistical
significance.

Inclusion Criteria:

- Only accepting participants in the Boston, Massachusetts area

- Age 21 to 75, male or female

- Willingness to eat prescribed diet for 4 weeks prior to infusion date, and 3.5 days
after the infusion date

- Willingness to participate in an infusion protocol, which will require them to stay
at the Center for Clinical Investigation (CCI) for one night and return for blood
draws every day for the next 3 days.

- Body Mass Index (BMI) 25-35 Kg/m2

- HDL<45 mg/dL for men, <55 mg/dL for women

Exclusion Criteria:

- Hematocrit <33

- Low-density Lipoprotein (LDL) cholesterol >190 mg/dl

- HDL cholesterol <20 mg/dl, to exclude those with rare genetic HDL deficiency
syndromes

- Fasting Triglycerides >500 mg/dl to exclude those with risk of pancreatitis

- ApoE genotypes, E2E2, E2E4, and E4E4.

- Lipid lowering medications

- Hormone replacement therapy

- Other medicines that affect plasma lipid levels: e.g. beta blockers, certain
psychiatric medicines including Alprazolam, Chlordiazepoxide, Clonazepam, Diazepam,
Lorazepam, Oxazepam, Prazepam, Aripiprazole, Chlorpromazine, Chlorprothixene,
Clozapine, Flupenthixol, Fluphenazine, Haloperidol, Loxapine, Mesoridazine,
Methotrimeprazine, Molindone, Olanzapine, Perphenazine, Pimozide, Pipotiazine,
Prochlorperazine, Promazine, Promethazine, Quetiapine, Risperidone, Sulpiride,
Thioridazine, Thiothixene, Trifluoperazine, Ziprasidone.

- Thyrotrophin-stimulating hormone: <0.5 or >5.0

- alanine aminotransferase : 1.5 x uln or 60 IU/L

- Aspartate transaminase: 1.5 x uln or 60 IU/L

- Bilirubin: outside upper limit. (>1.2 mg/dL)

- Creatinine: outside upper limit (>1.00 mg/dL)

- Diabetes by history

- Diabetes by fasting or post-challenge glycemia according to ADA guidelines:

- Fasting hyperglycemia (glucose >126 mg/dl).

- Post-challenge glucose by standard oral glucose tolerance test, >200 mg/dl

- Will not eat the provided diet and abstain from alcoholic beverages.

- Women who are pregnant