Direct association between the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 and plasma mevalonic acid and lathosterol concentrations in man.

Apolipoprotein B-100 (apo B) is the principal structural and functional protein of the pro-atherogenic lipoproteins, but its homeostasis in man has not been clearly established. The hepatic availability of cholesterol substrate may be a determining factor. We examined whether there was a direct correlation between plasma concentrations of mevalonic acid (MVA) and lathosterol (indices of in vivo cholesterol synthesis) and hepatic secretion of very-low-density lipoprotein (VLDL) apo B in 13 normolipidaemic, healthy male subjects. The secretion of VLDL apo B was measured using a primed constant intravenous infusion of 1-[13C]-leucine (1 mg/kg per h) over 8 h. Gas-chromatography mass spectrometry (GCMS) was used to derive isotopic enrichment of apo B and fractional turnover rate was calculated using a monoexponential function. There was a highly significant positive correlation between the absolute secretion rate (ASR) of VLDL apo B and the plasma concentrations of mevalonic acid (r = 0.72, P = 0.005) and lathosterol (r = 0.81, P = 0.001) and the lathosterol:cholesterol ratio (r = 0.79, P = 0.001). In multiple regression analysis, these correlations remained significant after adjusting for waist circumference, age, apolipoprotein E genotype and dietary fat intake. The data further support the notion that the availability of cholesterol substrate regulates the hepatic secretion rate of apo B.