The regulation of apolipoprotein B-100 (apo B) metabolism in man is not fully understood. In vitro studies suggest a key role for the hepatic availability of cholesterol substrate. We therefore examined whether there was a direct association between plasma mevalonic acid (MVA) concentration (an index of in vivo cholesterol synthesis) and hepatic secretion of very-lowdensity lipoprotein (VLDL) apo B in eight normolipidemic, healthy adult subjects. Hepatic secretion of VLDL apo B was estimated by endogenous labeling of apo B with an 8-hour primed, constant infusion of 1-13C-leucine. Isotopic enrichment of VLDL apo B was measured by gas chromatography-mass spectrometry (GCMS), from which the fractional secretion rate (FSR) was derived by a modified monoexponential function. Plasma concentration of MVA was measured by gas chromatographyelectron-capture mass spectrometry in blood samples taken at 9 AM. The absolute secretion rate (ASR) of VLDL apo B (mean -+ SD) was 9.7 -+ 2.6 mg/kg/d, and MVA concentration was 5.0 +_ 2.5 ng/mL. There was a highly significant positive correlation between ASR of VLDL apoB and plasma MVA (r = .88, P = .004), which persisted after adjusting for apo E phenotype. The findings suggest that in vivo cholesterol synthesis is a determinant of hepatic secretion of apo B in normolipidemic subjects, Copyright © 1995 by W,B. Saunders Company POLIPOPROTEIN B-100 (apo B) is the major structural protein of the proatherogenic plasma lipoproteins. I Apo B is synthesized almost exclusively in the liver, and its hepatic secretion is an important determinant of both plasma lipid levels and risk of atherosclerosis. 1-3 The respective roles of cholesterol ester and triglyceride in regulating apo B secretion have recently been reviewed. 4 Results of experimental studies suggest that the availability of intracellular cholesterol plays a key role in regulating apo B secretion. 5-8 However, the opposite conclusion was reached in more recent studies with Hep G2 cells, which showed that triglyceride synthesis was the major determinant. 9 The availability of free fatty acids may also regulate apo B secretion by controlling the rate of both cholesterol and triglyceride synthesis. 4,6 A perfused-rat liver preparation suggested that cholesterol ester competes with triglyceride for the lipid core of very-low-density lipoprotein (VLDL) particles and that cholesterol feeding can stimulate VLDL secretion3 ° Furthermore, in a patient with cholesterol ester storage disease, pharmacologic inhibition of cholesterol synthesis decreased VLDL apo B secretion, u However, there is as yet no evidence that under physiologic conditions rates of cholesterol synthesis and of hepatic secretion of apo B are closely coupled in man. The principal apo B-containing lipoprotein secreted by the liver is VLDL. Hepatic secretion of VLDL apo B may