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

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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.

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...

Overweight individuals with reduced insulin sensitivity often have mild to moderate hypertriglyceridemia. To investigate the role of apolipoprotein (apo)C-III metabolism in the etiology of hypertriglyceridemia in these individuals, we investigated 10 male subjects with different body weights (body mass index, 24-34 kg/m(2)) and insulin sensitivity (homeostasis model assessment, 4.7-35.0). Total plasma and very-low-density lipoprotein (VLDL) apoC-III kinetics, as well as VLDL triglyceride (TG) and VLDL apoB kinetics, were measured with iv injected stable isotopes. The apoC-III, TG, and apoB levels in VLDL ranged from 2.9-18.2 mg/dl, 0.49-2.89 mmol/liter, and 6.7-29.3 mg/dl, respectively. Mean production rates (PRs) were: VLDL apoC-III, 20.2 +/- 4.1 micromol/d (range, 8.0-44.8); VLDL TG, 26.9 +/- 4.6 mmol/d (range, 10.2-51.1); and VLDL apoB, 4.4 +/- 0.8 micromol/d (range, 1.5-9.1). VLDL apoC-III PRs were significantly correlated with body mass index, homeostasis model assessment, and plasma TG (r = 0.66, P < 0.05; r = 0.80, P < 0.01; r = 0.95, P < 0.001, respectively). Similar correlations were found for plasma apoC-III PRs (r = 0.70, P < 0.05; r = 0.67, P < 0.05; r = 0.80, P < 0.01, respectively). Fractional catabolic rates (FCRs) were not significantly related to metabolic variables. VLDL TG levels were strongly related to VLDL apoC-III levels (r = 0.99, P < 0.001) and VLDL apoC-III PRs (r = 0.94, P < 0.001). VLDL apoC-III levels were more strongly correlated with VLDL TG PRs (r = 0.81, P < 0.01) than with VLDL TG FCRs or VLDL apoB FCRs (r = -0.53, P = 0.12; r = -0.37, P = 0.29). These results suggest that increased hepatic production of VLDL apoC-III is characteristic of subjects with higher body weights and lower levels of insulin sensitivity and is strongly related to the plasma concentration and level of production of VLDL TG.