Clearance of postprandial and lipolytically modified human HDL in rabbits and rats.

Triglyceride (TG) enrichment of high density lipoproteins (HDL) in hypertriglyceridemic states renders the particles vulnerable to lipolysis, which reduces their size. In the present study we modified the size and composition of HDL in vivo in hypertriglyceridemic humans by administering a bolus of intravenous heparin, and tested the subsequent clearance of the isolated HDL particles in rabbits and rats. HDL was isolated by ultracentrifugation from 21 moderately hypertriglyceridemic humans, 5 h after ingestion of a high fat meal and then 15 min after an intravenous heparin bolus (60 U/kg). Postprandial large TG-rich preheparin HDL and small, TG-poor postheparin HDL were labeled with either 125I or 131I. The clearance of apoA-I associated with each HDL tracer was determined by injecting the tracers 1) simultaneously (n = 13) and 2) sequentially (n = 8) into male New Zealand White rabbits, an hepatic lipase-deficient animal, and 3) by injecting the tracers simultaneously into male Sprague-Dawley rats (n = 8), an animal that has hepatic lipase. Die-away curves of each radiolabeled tracer were analyzed using a two-pool model that assumes the existence of an intravascular pool in dynamic equilibrium with an extravascular pool. In the rabbit studies, the fractional catabolic rate (FCR) of small, postheparin TG-poor HDL was greater than the FCR of the larger TG-rich HDL (11% greater in the simultaneous study, P < 0.001, and 45% greater in the sequential study, P < 0.001). Opposite results were observed in rats as large TG-rich preheparin particles showed a greater FCR (1.8-fold) than smaller TG-poor postheparin HDL (P < 0.05). These data suggest that although size and composition of HDL can influence its catabolism, the effect is not always in the same direction and depends on other factors present in vivo.

Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans.

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 131I-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 approximately 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 of VLDL production by insulin in vivo is only partly due to the suppression of plasma FFA, and may also be due to an FFA-independent process.

Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals.

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.