S. Narasimha Rao

In order to gain further insight into the relationship between high-density lipoprotein (HDL) metabolism and plasma triglyceride transport, measurements were made of HDL cholesterol concentration, apoprotein (apo) AI and AII metabolism, very-low-density-lipoprotein (VLDL) apo B metabolism, and heparin-elutable adipose tissue lipoprotein lipase (LPL) activity in seventeen subjects with a wide range of plasma triglyceride concentrations (0.8-25 mmol/l). The fractional catabolic rate (FCR) of VLDL apo B was directly related to LPL activity (r = +0.80), providing evidence that the activity of the enzyme in adipose tissue is a determinant of the rate of lipolysis of VLDL in man. HDL cholesterol concentration was a positive function of both VLDL apo B FCR (r = +0.74) and LPL activity, a finding consistent with previous evidence for the origin of a proportion of HDL cholesterol from 'surface remnants' liberated during VLDL catabolism. THe FCRs of both apo AI and apo AII were inversely related to VLDL apo B FCR (AI, r = -0.52; AII, r = -0.69) and to LPL activity. The synthetic rate of ap AII, but not that of apo AI, was positively correlated with VLDL apo B synthesis (r = +0.7 1). Thus, the metabolism of the major proteins of HDl in man appears to be closely associated with VLDL metabolism.

The mechanisms by which dietary fat influences fasting plasma lipid concentrations have been investigated in hyperlipidaemic subjects. The synthetic and fractional catabolic (FCR) rates of the apoprotein B (apo B) of very-low density (VLDL) and low-density (LDL) lipoproteins were measured using radioiodinated autologous lipoproteins. Reductions of LDL concentration in eight subjects during low-fat (25% of energy) diets were largely explained by diminished synthesis (-20%, P less than 0.02), and possibly also by an increased FCR (+15%, P = 0.05) of LDL, compared with observations made during a high-fat (45% of energy) diet of similar fatty acid composition. VLDL apo B synthesis and FCR were not significantly altered. When a diet rich in polyunsaturated fatty acids was exchanged for one high in saturated fatty acids (fat providing 45% of energy on both occasions) in four subjects, the synthetic rates of both VLDL apo B (-31%, P less than 0.02) and LDL apo B (-23%, P less than 0.10) were reduced while their FCRs were unchanged.

Abstract. Plasma lipoproteins and apolipoproteins have been studied in a kindred with familial apolipoprotein CII (apo CII) deficiency. As in two other recently documented pedigrees, apo CII deficiency appeared to be transmitted as an autosomal recessive trait. The homozygous state was characterized by gross fasting hypertriglyceridaemia, complete absence of apo CII from plasma and failure of plasma to activate lipoprotein lipase. Post‐heparin plasma hepatic triglyceride lipase activity was normal. Hypertriglyceridaemia reflected chylomicronaemia and elevated Sf 100–400 and Sf 20–100 lipoprotein concentrations; lipoproteins of Sf 12–20 (LDL 1 ), Sf 0–12 (LDL 2 ), F 1.2 3.5–9 (HDL 2 ) and F 1.2 0–3.5 (HDL 3 ) were greatly reduced in concentration. Low density lipoproteins (1.006–1.063 g/ml), isolated by preparative ultracentrifugation, and high density lipoproteins, isolated by heparin/Mn ++ , were triglyceride‐enriched. Electroimmunoassays revealed additionally low plasma concentrations of apolipoproteins AI, AII and B and very high concentrations of apolipoproteins CIII and E in the homozygote. The parents of the proband (heterozygotes) were normotriglyceridaemic, and had normal lipoprotein lipid concentrations and normal apolipoprotein AI, AII, B, CIII and E concentrations, in spite of having low apo CII concentrations. Activation of lipoprotein lipase in the homozygote by intravenous infusion of 200 ml fresh‐frozen plasma rapidly reduced the plasma concentrations of chylomicrons and very low density lipoproteins (VLDL). Within VLDL, the decrease in concentration occurred sequentially in the Sf 100–400 and Sf 20–100 subclasses. These changes were associated during a 4‐day study period with reciprocal increases in LDL 1 , LDL 2 , HDL 2 and HDL 3 . The plasma concentrations of apo AI and apo B also increased, associated with a less marked fall in that of apo CIII; the apo AII and apo E concentrations were unchanged. These observations support other evidence that apo CII is a cofactor for the catabolism of chylomicrons and both major subfractions of VLDL by lipoprotein lipase in man, and that human LDL 1 and LDL 2 are derived, at least in part, from triglyceride‐rich lipoprotein catabolism. They also suggest that both major subfractions of HDL acquire additional components during triglyceride‐rich lipoprotein catabolism. In normal subjects the plasma apo CII concentration appears to be greatly in excess of that required for adequate activation of lipoprotein lipase.

1. The metabolism of the major proteins of plasma high-density lipoprotein (HDL), apoproteins AI and AII, have been studied in 10 normotriglyceridaemic subjects and in 11 hypertriglyceridaemic subjects (plasma triglyceride 4.5--25 mmol/l) by kinetic analysis of the plasma specific radioactivity versus time curves of the apoproteins after intravenous injection of autologous 125I-labelled high-density lipoprotein. 2. The specific radioactivity versus time curves of both apoproteins (followed for 14 days) were bi-exponential in all subjects. 3. The plasma apoprotein AI and AII concentrations were significantly lower in the hypertriglyceridaemic subjects than in the normotriglyceridaemic subjects. Kinetic analysis showed that this was associated with a lower rate of synthesis of apoprotein AI (P < 0.01) and a higher fractional catabolic rate of apoprotein AII (P < 0.01) in the hypertriglyceridaemic group. 4. There were no significant differences between the two groups in the synthetic rate of apoprotein AII, the fractional catabolic rate of apoprotein AI or the intravascular/extravascular distributions of the apoproteins. 5. Thus hypertriglyceridaemia appears to be frequently associated with divergent abnormalities of the metabolism of the major high density lipoprotein apoproteins.