Changes in VLDL triglyceride and VLDL apo B production were determined semiquantitatively in healthy young men by examining the effect of altering plasma insulin and/or FFA levels on the change in the slopes of the specific activity of VLDL [3H]triglyceride glycerol or the "'I-VLDL apo B versus time curves.In one study (n = 8) insulin was infused for 5 h using the euglycemic hyperinsulinemic clamp technique. Plasma FFA levels declined by 80% (0.52±0.01 to 0.11±0.02 mmol/liter), VLDL triglyceride production decreased by 66.7±4.2% (P = 0.0001) and VLDL apo B production decreased by 51.7±10.6% (P = 0.003). In a second study (n = 8) heparin and Intralipid (Baxter Corp., Toronto, Canada) were infused with insulin to prevent the insulin-mediated fall in plasma FFA levels. Plasma FFA increased approximately twofold (0.43±0.05 to 0.82 + 0.13 mmol/liter), VLDL triglyceride production decreased to a lesser extent than with insulin alone (P = 0.006) (-31.8±9.5%, decrease from baseline P = 0.03) and VLDL apo B production did not decrease significantly ( -6.3±13.6%, P = NS). In a third study (n = 8) when heparin and Intralipid were infused without insulin, FFA levels rose approximately twofold (0.53±0.04 to 0.85±0.1 mmol/liter), VLDL triglyceride production increased by 180.1±45.7% (P = 0.008) and VLDL apo B production increased by 94.2+28.7% (P = 0.05). We confirm our previous observation that acute hyperinsulinemia suppresses VLDL triglyceride and VLDL apo B production in healthy humans. In addition, we have demonstrated that elevation of plasma FFA levels acutely stimulates VLDL production in vivo in healthy young males. Elevating plasma FFA during hyperinsulinemia attenuates but does not completely abolish the suppressive effect of insulin on VLDL production, at least with respect to VLDL triglycerides. Therefore, in normal individuals the acute inhibition This work was presented in part at

Women with SLE have a range of detectable coronary risk factors that are not fully reflected in the Framingham risk factor formula. These factors are likely to contribute to the loss of protection from CHD that has been observed in SLE.

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The effects of short-term hyperinsulinemia on the production of both VLDL triglyceride and VLDL apoB were determined semiquantitatively before and during a 6-h euglycemic hyperinsulinemic clamp (40 mU.m-2 x min-1) in 17 women (8 chronically hyperinsulinemic obese, BMI = 35.7 kg/m2; 9 normal weight, BMI = 22.5 kg/m2). During acute hyperinsulinemia, plasma FFA decreased by approximately 95% within 1 h in both groups. VLDL triglyceride production decreased 66% in the control subjects (P = 0.0003) and 67% in obese subjects (P = 0.0003). ApoB production decreased 53% in control subjects (P = 0.03) but only 8% in obese (NS). Plasma triglycerides decreased by 40% from baseline in control subjects (P < 0.0001) but only by 10% in obese subjects (P = NS). Despite the similar decrease in triglyceride and apoB production in control subjects, VLDL particle size (triglyceride-to-apoB ratio) decreased with hyperinsulinemia (P = 0.003). In obese subjects, despite a decrease in triglyceride production similar to that in control subjects but no change in apoB production, VLDL size did not change appreciably. Acute hyperinsulinemia in humans: 1) suppresses plasma FFA equally in control and obese subjects at this high dose of insulin; 2) inhibits VLDL triglyceride production equally in control and obese subjects, perhaps secondary to the decrease in FFA; 3) inhibits VLDL apoB production in control but less so in obese subjects, suggesting that obese subjects may be resistant to this effect of insulin; 4) decreases plasma triglyceride and VLDL particle size in control subjects, reflecting either stimulation of LPL activity or a greater relative decrease in triglyceride to apoB production; and 5) does not decrease plasma triglyceride or VLDL size in obese subjects to the same extent as it does in control subjects. Thus, the insulin resistance of obesity affects some but not all aspects of VLDL metabolism.

A 59-year-old man with severe hypertriglyceridemia and no post-heparin lipolytic activity was studied because of a marked fall in plasma triglyceride concentrations after a blood transfusion. An apolipoprotein activator (apolipoprotein C-II) for lipoprotein lipase could not be detected by polyacrylamide-gel electrophoresis of apoproteins, immunodiffusion of the plasma against anti-apolipoprotein CII or activation assays for lipoprotein lipase. Furthermore, the patient's triglyceride-rich lipoproteins would not serve as substrate for lipoprotein lipase. The patient had latent post-heparin lipolytic activity, which appeared after the addition of apolipoprotein CII to the post-heparin plasma. After a transfusion of 1 unit of plasma from a normal subject the patient's plasma triglycerides fell, within one day, from 1000 to 250 mg per deciliter and remained below preinfusion concentrations for six days. We conclude that this patient's hyperlipoproteinemia resulted from a deficiency of apolipoprotein C-II.

Abstract-Plasma cholesteryl ester transfer protein (CETP) facilitates intravascular lipoprotein remodeling by promoting the heteroexchange of neutral lipids. To determine whether the degree of triglyceridemia may influence the CETP-mediated redistribution of HDL CE between atherogenic plasma lipoprotein particles in type 2 diabetes, we evaluated CE mass transfer from HDL to apoB-containing lipoprotein acceptors in the plasma of type 2 diabetes subjects (nϭ38). In parallel, we investigated the potential relationship between CE transfer and the appearance of an atherogenic dense LDL profile. The diabetic population was divided into 3 subgroups according to fasting plasma triglyceride (TG) levels: group 1 (G1), TGϽ100 mg/dL; group 2 (G2), 100ϽTGϽ200 mg/dL; and group 3 (G3), TGϾ200 mg/dL. Type 2 diabetes patients displayed an asymmetrical LDL profile in which the dense LDL subfractions predominated. Plasma levels of dense LDL subfractions were strongly positively correlated with those of plasma triglyceride (TG) (rϭ0.471; Pϭ0.0003). The rate of CE mass transfer from HDL to apoB-containing lipoproteins was significantly enhanced in G3 compared with G2 or G1 (46.2Ϯ8.1, 33.6Ϯ5.3, and 28.2Ϯ2.7 g CE transferred ⅐ h Ϫ1 ⅐ mL Ϫ1 in G3, G2, and G1, respectively; PϽ0.0001 G3 versus G1, Pϭ0.0001 G2 versus G1, and Pϭ0.02 G2 versus G3). The relative capacities of VLDL and LDL to act as acceptors of CE from HDL were distinct between type 2 diabetes subgroups. LDL particles represented the preferential CE acceptor in G1 and accounted for 74% of total CE transferred from HDL. By contrast, in G2 and G3, TG-rich lipoprotein subfractions accounted for 47% and 72% of total CE transferred from HDL, respectively. Moreover, the relative proportion of CE transferred from HDL to VLDL 1 in type 2 diabetes patients increased progressively with increase in plasma TG levels. The VLDL 1 subfraction accounted for 34%, 43%, and 52% of total CE transferred from HDL to TG-rich lipoproteins in patients from G1, G2, and G3, respectively. Finally, dense LDL acquired an average of 45% of total CE transferred from HDL to LDL in type 2 diabetes patients. In conclusion, CETP contributes significantly to the formation of small dense LDL particles in type 2 diabetes by a preferential CE transfer from HDL to small dense LDL, as well as through an indirect mechanism involving an enhanced CE transfer from HDL to VLDL 1 , the specific precursors of small dense LDL particles in plasma. T he most common alterations in lipid and lipoprotein profile in type 2 diabetes involve an elevation in both postprandial and fasting plasma triglyceride (TG) and VLDL concentrations, a dense LDL phenotype, and low levels of HDL cholesterol. 1 Hypertriglyceridemia contributes significantly to the increased risk for premature cardiovascular disease in type 2 diabetes. 2 There is a strong positive correlation between plasma concentrations of TG and small dense LDL in nondiabetic subjects, suggesting that plasma TG concentrations influence LDL subclass distribution. 3 The particle si...

The metabolism of chylomicron remnants and VLDL was studied in healthy controls and normo-(NTG) and hypertriglyceridemic (HTG) patients with coronary artery disease after intake of an oral fat load. Specific determination of apo B-48 and B-100 enabled separation of the respective contribution of the two lipoprotein species. The postprandial plasma levels of small (Sf 20-60) and large (Sf 60-400) chylomicron remnants increased in controls and NTG patients. In contrast, only large chylomicron remnants increased in the HTG patients. An increase of large VLDL was seen in response to the oral fat load in all groups, whereas small VLDL were either unchanged in the controls and the NTG patients, or decreased in the HTG patient group. The whole plasma concentration of C apolipoproteins was essentially uninfluenced by the oral fat load, whereas the content in large triglyceride-rich lipoproteins paralleled the apo B elevations in controls and NTG patients. An even more prominent increase of apo B in large triglyceriderich lipoproteins in the HTG group was not accompanied by an increase of C apolipoproteins. These findings indicate that chylomicrons compete with VLDL for removal of triglycerides by lipoprotein lipase and that the postprandial metabolism of triglyceride-rich lipoproteins is severely defective in hypertriglyceridemia. (J. Clin. Invest. 1993.91:748-758.) Key words: chylomicron remnants * very low density lipoprotein -apolipoprotein B-48 * apolipoprotein B-100 * apolipoprotein C-I1

The inverse relationship between plasma HDL cholesterol concentrations and the risk of cardiovascular disease is well accepted (1, 2). There is a large body of evidence indicating that variations in plasma HDL cholesterol concentrations are inversely related to plasma triglyceride (TG) levels (3, 4). Hence, one of the most frequent metabolic abnormalities accompanying reduced plasma HDL cholesterol levels is hypertriglyceridemia. Apo A-I, the major protein of HDL, is a crucial structural and functional component in the metabolism of these particles. Studies have shown that the fractional catabolic rate (FCR) of apo A-I is a significant and powerful predictor of plasma HDL cholesterol levels (5, 6). Studies that have examined the production and clearance rates of apo A-I as a marker of HDL metabolism in humans have led to the hypothesis that hypertriglyceridemia may be one of several factors ultimately affecting plasma HDL cholesterol levels (7-9). However, these studies have not tested this hypothesis directly because they relied on correlations between HDL apo A-I FCR and plasma TG concentrations.The mechanisms underlying the enhanced catabolism of apo A-I in hypertriglyceridemic states are not well understood. Hypertriglyceridemia is associated with an increased cholesteryl ester transfer protein-mediated (CETP-mediated) transfer of TG from the expanded pool of TG-rich lipoproteins to HDL and of cholesteryl ester from HDL to TG-rich lipoproteins (10). The resulting TG enrichment of the HDL particle makes it a better substrate for lipolysis by hepatic lipase, an enzyme that plays a key role in HDL metabolism (11,12). Results from an ex vivo kidney perfusion study have indicated that TG enrichment of HDL alone, in the absence of subsequent lipolytic modification of the particle by hepatic lipase and lipoprotein lipase, may have very little impact, if any, on the uptake of apo A-I by the kidney (13). On the other hand, lipolytic modification of TG-rich HDL by lipoprotein lipase and hepatic lipase was associated with a significant increase in the uptake of apo A-I by the perfused rabbit kidney and loss of apo A-I from the HDL fraction (13). In vitro incubation of TG-enriched human HDL with hepatic lipase has also been shown to promote the loss of apo A-I from the particle (14). We have recently shown, using a rabbit model, that the FCR of apo A-I from small, lipolytically modified HDL was increased significantly compared with the FCR of apo A-I from large, TG-enriched HDL (15). This increase in HDL FCR was not observed in the absence of lipolytic modification of TG-rich HDL particles (16). In vitro and in vivo data sug- Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plas...