1. We measured the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 (VLDL apoB) using a stable-isotope gas chromatography—mass spectrometry method in six obese subjects [three males, three females, age 41.5 ± 3.4 years (mean ± SEM), weight 105.0 ± 4.8 kg, plasma total cholesterol concentration 6.2 ± 0.4 mmol/l, triacylglycerol 2.8 ± 0.8 mmol/l, high-density lipoprotein cholesterol 1.0 ± 0.2 mmol/l] and six lean control subjects (three males, three females, age 41.8 ± 3.7 years, weight 68.2 ± 4.9 kg, total cholesterol concentration 4.5 ± 0.3 mmol/l, triacylglycerol 0.8 ± 0.2 mmol/l, high-density lipoprotein cholesterol 1.3 ± 0.1 mmol/l).
2. Plasma total cholesterol, triacylglycerol and mevalonic acid (an index of cholesterol synthesis in vivo) concentrations were significantly higher in the obese subjects than in control subjects (P = 0.02, P = 0.03, P = 0.04, respectively). VLDL apoB pool size and absolute secretion rate were significantly higher in the obese subjects than in control subjects (323.4 ± 99.8 mg versus 53.6 ± 17.1 mg, P = 0.004; and 42.3 ± 13.8 mg kg fat-free mass−1 day−1 versus 10.7 ± 0.4 mg kg fat-free mass−1 day−1, P = 0.01), but there was no significant difference in the fractional catabolic rate of VLDL apoB.
3. After pooling obese and control data, there was a significant positive association between VLDL apoB absolute secretion rate and (i) fat mass (r = 0.71, P = 0.009), (ii) plasma total cholesterol (r = 0.66, P = 0.019), (iii) triacylglycerol (r = 0.72, P = 0.008), (iv) total apolipoprotein B-100 (r = 0.77, P = 0.02), (v) mevalonic acid (r = 0.81, P < 0.001), (vi) fasting insulin (r = 0.61, P = 0.03) and (vii) fasting C-peptide (r = 0.70, P = 0.01) concentrations. There was also a significant positive association between plasma insulin and plasma mevalonic acid concentrations (r = 0.59, P = 0.04). The association between VLDL apoB absolute secretion rate and plasma mevalonic acid concentration remained significant after adjusting for plasma insulin concentration (r = 0.83, P = 0.01); however plasma insulin concentration was no longer associated with VLDL apoB absolute secretion rate (P = 0.40).
4. We conclude that increased hepatic secretion of VLDL apoB contributes to the elevated lipid concentrations observed in obesity. We suggest that increased secretion of this apolipoprotein may be a consequence of resistance to the inhibitory effect of insulin on VLDL apoB secretion and may be partly mediated by increased cholesterol synthesis.