Increased hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 in heterozygous familial hypercholesterolaemia: a stable isotope study

• Published in: Atherosclerosis 1995-02, Vol.113 (1), p.79-89
• Main Authors: Cummings, Michael H., Watts, Gerald F., Umpleby, Margot, Hennessy, Thomas R., Quiney, Jeremy R., Sönksen, Peter H.
• Format: Article
• Language: English
• Subjects: Adult; Apolipoprotein B; Apolipoprotein B-100; Apolipoproteins B - blood; Apolipoproteins B - metabolism; Biological and medical sciences; Carbon Isotopes; Cholesterol, HDL - blood; Cholesterol, LDL - blood; Disorders of blood lipids. Hyperlipoproteinemia; Female; Gas Chromatography-Mass Spectrometry; Heterozygote; Heterozygous familial hypercholesterolaemia; Humans; Hyperlipoproteinemia Type II - blood; Hyperlipoproteinemia Type II - genetics; Hyperlipoproteinemia Type II - metabolism; Lipoproteins, LDL - blood; Lipoproteins, VLDL - blood; Lipoproteins, VLDL - metabolism; Liver - metabolism; Male; Medical sciences; Metabolic diseases; Middle Aged; Regression Analysis; Stable isotopes; Triglycerides - blood; Very-low-density lipoprotein
• ISSN: 0021-9150; 1879-1484
• DOI: 10.1016/0021-9150(94)05430-Q

We have measured the hepatic secretion of very-low-density-lipoprotein apolipoprotein B-100 (VLDL apo B) in 6 patients with heterozygous familial hypercholesterolaemia (FH) (4 males, 2 females, age 47.0 ± 2.7 years (mean ± S.E.M.), weight 71.0 ± 5.3 kg) and 6 normocholesterolaemic subjects matched for age, weight and sex (4 males, 2 females, age 47.5 ± 3.1 years, weight 70.0 ± 4.4 kg) using a stable isotope method. Each subject received a primed, constant infusion of [1- 13C]leucine and isotopic enrichment of VLDL apo B was determined using gaschromatography mass-spectrometry (GCMS). Mean plasma low-density-lipoprotein (LDL) cholesterol and apo B concentrations in the FH group were more than twice that in the control group (FH, 8.5 ± 0.5 mmol/l vs. controls, 3.3 ± 0.2 mmol/l, P < 0.001; and FH, 2.0 ± 0.1 g/l vs. controls, 1.0 ± 0.04 g/l, P < 0.0001, respectively). Plasma triglyceride (TG) and high-density-lipoprotein (HDL) cholesterol concentrations were not significantly different between the two groups. Although the fractional secretion rates of VLDL apo B were similar (FH, 14.3 ± 3.6 pools/day vs. controls, 11.6 ± 1.7 pools/day, P = 0.53), VLDL apo B pool size and VLDL apo B absolute secretion rates (ASR) were significantly higher in the FH group (FH, 234.2 ± 27.8 mg vs. controls, 66.3 ± 13.5 mg, P < 0.001; and FH, 51.4 ± 17.9 mg/kg per day vs. controls, 9.4 ± 1.1 mg/kg per day, P < 0.02, respectively). We conclude that FH is associated with increased hepatic secretion of VLDL apo B and that this may contribute to the elevated concentration of LDL-cholesterol. The findings are also consistent with the hypothesis that in FH increased hepatic cholesterol availability (due to increased uptake of LDL-cholesterol via the receptor-independent pathway) stimulates hepatic secretion of VLDL apo B.