The Effects of Fat and Theobromine on apoA-I

Rationale: Despite successful efforts to lower atherogenic serum low-density lipoprotein (LDL) cholesterol concentrations, a substantial residual cardiovascular risk is still present. An additive strategy to further lower this residual risk may be via raising high-density lipoprotein (HDL) cholesterol concentrations, and in particular those of its major protein constituent apolipoprotein A-I (apoA-I). However, recent evidence shows that raising HDL cholesterol (HDL-C) concentrations not always causes a reduction in cardiovascular disease (CVD) risk. To understand this it is important to know what are the targets and molecular mechanisms that underlie a shift to a HDL fraction with cardioprotective activities. There is increasing evidence that particularly the apoA-I proteins in the HDL fractions are atheroprotective. It is important to verify whether the effect of an intervention actually increases apoA-I production since that results in the formation of de-novo small pre-beta HDL particles that have full capacity to resorb cholesterol from the arterial wall and return this to the liver for secretion (reverse cholesterol transport). The investigators here propose to evaluate, in a double-blind human intervention study, the difference in intestinal apoA-I gene expression, of healthy subjects, after consumption of a high fat (HF) or low fat (LF) meal. Additionally the investigators propose to evaluate the effect of theobromine on intestinal apoA-I expression. Based on several studies, theobromine improved cardiovascular risk parameters among which an elevation in apoA-I and HDL cholesterol concentrations. It is however unknown whether this effect of theobromine originates from elevated apoA-I production, which suggest improved functionality, or decreased clearance, suggesting reduced functionality. The investigators therefore propose to also evaluate if the usage of theobromine is a better way to increase intestinal apoA-I mRNA and protein expression, than consumption of a HF meal. The investigators will do this in the same double-blind human intervention study. The theobromine will be added in a third arm in a LF condition.

Study design: The proposed study will have a randomized, double-blind cross-over design. The total study duration will be 17 days, consisting of 3 experimental days with postprandial tests, each separated by a 1 week wash-out period.

Study population: Ten apparently healthy male subjects, aged 18-60 years, without a history of any gastrointestinal disorders or complaints.

Intervention: During the three experimental days, subjects will consume a milkshake: one HF milkshake, one LF milkshake and one LF milkshake supplemented with 850 mg theobromine. Total follow-up during each of the postprandial tests is 5 hours.