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 bi osynthesis of serum cholesterol and very low density lipoprotein (VLDL )-palmitate. The isotopic enrichment of the true biosynthetic precurso r (intracellular acetyl-CoA) during oral or intravenous administration of sodium[1-C-13]- or [2-C-13]acetate was calculated from mass isotop omer fractional abundances in free cholesterol and VLDL-palmitate, det ermined by gas chromatography-mass spectrometry (GC-MS). To convert fr actional into absolute cholesterol synthesis rates, decay rate constan ts of plasma cholesterol were determined from the die-away curves of e ndogenously labeled high-mass isotopomers. Oral [C-13]acetate was a 3- 4 times more efficient means of labeling the precursor pool for VLDL-p almitate than was intravenous [C-13]acetate, consistent with a splanch nic 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 c holesterol was 8-11 mg/kg per day (an estimated 65-75% of input into s erum cholesterol); it was 1.5- to 3-fold higher at night than during t he 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, e ndogenous synthesis of fatty acids made a relatively minor contributio n 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 influen ced by menstrual cycle (3-fold elevated in the follicular phase compar ed to the luteal phase), and body composition (higher in obese men tha n normal weight men, r2 = 0.59 for lipogenesis vs. body mass index). F actors responsible for periodicities in endogenous lipid synthesis can be studied in humans using this approach.