INCREASED HEPATIC SECRETION OF VERY-LOW-DENSITY LIPOPROTEIN APOLIPOPROTEIN B-100 IN OBESITY - A STABLE-ISOTOPE STUDY

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, tri-acylglycerol 2.8+/-0.8 mmol/I, 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 423+/-13.8 mg kg fat-free mass(-1) day(-1) versus 10.7+/- 0.4 mgkg 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.