Quantification of menstrual and diurnal periodicities in rates of cholesterol and fat synthesis in humans.

The mass isotopomer distribution analysis (MIDA) technique is applied here in men and menstruating women to quantify periodicities in the biosynthesis of serum cholesterol and very low density lipoprotein (VLDL)-palmitate. The isotopic enrichment of the true biosynthetic precursor (intracellular acetyl-CoA) during oral or intravenous administration of sodium[1-13C]- or [2-13C]acetate was calculated from mass isotopomer fractional abundances in free cholesterol and VLDL-palmitate, determined by gas chromatography-mass spectrometry (GC-MS). To convert fractional into absolute cholesterol synthesis rates, decay rate constants of plasma cholesterol were determined from the die-away curves of endogenously labeled high-mass isotopomers. Oral [13C]acetate was a 3-4 times more efficient means of labeling the precursor pool for VLDL-palmitate than was intravenous [13C]acetate, consistent with a splanchnic site of VLDL-fatty acid synthesis, whereas the precursor for free cholesterol had an intermediate enrichment, suggesting a contribution from extra-splanchnic tissues as well. Endogenous synthesis of serum cholesterol was 8-11 mg/kg per day (an estimated 65-75% of input into serum cholesterol); it was 1.5- to 3-fold higher at night than during the day (37-49 mg/h at night compared to 9-23 mg/h during the day) and did not vary over the menstrual cycle (608-697 mg/day). In contrast, endogenous synthesis of fatty acids made a relatively minor contribution to body fat pools (1/10-1/20) of input into VLDL-palmitate) compared to dietary fat intake; it was greater in the day-time, and was influenced by menstrual cycle (3-fold elevated in the follicular phase compared to the luteal phase), and body composition (higher in obese men than normal weight men, r2 = 0.59 for lipogenesis vs. body mass index). Factors responsible for periodicities in endogenous lipid synthesis can be studied in humans using this approach.