Compositional and metabolic heterogeneity of alpha 2- and beta-very-low-density lipoproteins in subjects with broad beta disease and endogenous hypertriglyceridemia

The catabolism of alpha 2- and beta-very-low-density lipoproteins (VLDL) was studied in normolipidemic and hyperlipidemic subjects to determine whether differences in the catabolism of these subfractions are due to their composition. alpha 2-VLDL (cholesterol/triglyceride ratio, 00.18 +/- 0.06; and apoprotein E/C ratio, 0.27 +/- 0.22, n = 4) and beta-VLDL (cholesterol/triglyceride ratio, 0.67 +/- 0.13; and apoprotein E/C ratio, 1.05 +/- 0.52, n = 4) were isolated from subjects with broad beta disease, iodinated, and injected in five normolipidemic subjects, six with broad beta disease, and five with endogenous hypertriglyceridemia. VLDL, intermediate (IDL) and low-density lipoprotein (LDL) apoprotein (apo)-B radioactivity (tetramethylurea insoluble) following injection of 125I-labeled alpha 2- and beta-VLDL decayed biphasically in all subjects, and this decay in normolipidemic subjects was more rapid than in subjects with broad beta disease (P = 0.004) or endogenous hypertriglyceridemia (P = 0.004 for alpha 2- and P = 0.010 for beta-VLDL). The residence times, however, for the delipidation chain in alpha 2-VLDL were similar in all the subjects and varied from three to six hours. The decay of radioactivity in beta-VLDL in subjects with broad beta disease was much slower (residence time, 36.9 +/- 24.4 hr, n = 7) than in normolipidemic subjects (residence time, 7.56 +/- 4.6 hr, n = 5) or in subjects with endogenous hypertriglyceridemia (residence time, 10.6 +/- 4.65, n = 4). The residence time for alpha 2-VLDL was longer than for beta-VLDL in all subjects, suggesting that alpha 2-VLDL is a precursor to beta-VLDL. To test this directly, iodinated alpha 2-VLDL was injected into a subject with broad beta disease and the radioactivity in the subfractions was followed. The radioactivity from alpha 2-VLDL was transferred into beta-VLDL supporting, the notion that alpha 2-VLDL generated some beta-VLDL. Nicotinic acid treatment of a subject with broad beta disease accelerated the catabolism of alpha 2- and beta-VLDL without changing the VLDL composition.     

Studies on the metabolic mechanism of reduced high density lipoproteins during anabolic steroid therapy

To explore the mechanism whereby stanozolol, a 17 alpha-methyl androgenic anabolic steroid, depresses high density lipoproteins (HDL), 6 subjects, aged 46-71 yr (4 postmenopausal women and 2 men), underwent paired studies of 125I-HDL turnover (including HDL2 and HDL3 and Apo A-I and A-II) and postheparin plasma (PHP) lipolytic activity (hepatic triglyceride lipase, HTGL, and lipoprotein lipase LPL) before and during treatment with stanozolol, 6 mg/day. While total cholesterol and triglyceride levels did not change during stanozolol, HDL-cholesterol decreased from 59 +/- 18 mg/dl (x +/- SD) to 29 +/- 7 mg/dl (p less than 0.01) and low density lipoprotein (LDL)-cholesterol increased from 160 +/- 36 mg/dl to 181 +/- 42 mg/dl (p less than 0.02). PHP-HTGL increased from 111 +/- 47 nmole/min/ml to 369 +/- 202 nmole/min/ml (p less than 0.04), while PHP-LPL did not change. At baseline the residence time of HDL2 (4.00 +/- 1.04 day) was shorter than that of HDL3 (6.79 +/- 1.00 day) (p less than 0.001). Residence times of both declined on stanozolol, to 3.25 +/- 0.83 day and 4.00 +/- 0.29 day, respectively (0.1 less than p less than 0.2); however, only the reduction in residence time of HDL3 was statistically significant (p less than 0.001). At baseline the residence time of apo A-I (4.93 +/- 1.32 day) was shorter than that of A-II (6.85 +/- 1.98 day) (p less than 0.025); on stanozolol these declined to 3.19 +/- 0.41 (p less than 0.02) and 5.10 +/- 1.13 (p = 0.07), respectively, still significantly different from each other (p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)     

Exogenous estrogens attenuate dietary hypercholesterolemia and atherosclerosis in the rabbit

The effect of exogenous estrogens upon the response to dietary cholesterol was tested in New Zealand White rabbits. Cholesterol-fed, untreated rabbits had a 10-fold increase in plasma cholesterol in 12 wk. The major increase of cholesterol occurred in very low density lipoproteins (VLDL, 43.5-fold) followed by intermediate density lipoproteins (IDL, 26-fold) and low density lipoproteins (LDL, 6-fold) with no change in high density lipoproteins (HDL). These diet induced changes were markedly attenuated in the estrogen treated animals, in whom plasma cholesterol increased only 5-fold. This increase was distributed among LDL (6-fold), IDL (7.5-fold), and VLDL (9-fold), similarly with no change in HDL. All the lipoproteins in both groups of animals were considerably enriched in cholesterol during cholesterol feeding as indicated by a high cholesterol/protein and cholesterol/triglyceride ratio. However, these ratios were lower in estrogen treated animals. There were no differences in the feed consumption, body weight or cholesterol absorption between the two groups of animals. Rabbits fed a cholesterol-rich diet but not treated with estrogen had well developed lesions in all parts of the aorta with higher content of cholesterol and phospholipids as compared to those injected with estrogen, whose aortas were completely clear of visible atherosclerosis. Equivalent total hypercholesterolemia was induced in other estrogen-treated rabbits by feeding twice the cholesterol dietary content (0.2%) as in nonestrogen-treated animals. Aortic atherosclerosis was far more evident in the latter, which had higher proportions of cholesterol-rich lipoproteins of d < 1.006 g/ml.     

Effect of diet-induced hypercholesterolemia on high density lipoprotein metabolism in pigtail monkeys (Macaca nemestrina)

Pigtail monkeys (Macaca nemestrina) were used as model animals to study the compositional and metabolic changes induced in high density lipoproteins (HDL) by diet-induced hypercholesterolemia. Feeding a high cholesterol and high saturated fat (HCHF) diet to monkeys for 9 mo increased their plasma cholesterol (fourfold) and phospholipids (twofold) but decreased HDL cholesterol, phospholipids, triglycerides, and proteins to 60%, 65%, 10%, and 50%, respectively, of those in control animals. The two major apolipoproteins of HDL (A-I and A-II) had a 2.4:1 ratio in control animals; this was raised to 4:1 in HCHF-fed animals attributable to a greater decrease in A-II. HDL turnover studies suggested that normal HDL was catabolized faster than HDL from HCHF donors in both normal and HCHF-fed recipients. HCHF-fed recipients, however, catabolized HDL from both normal and HCHF-fed donors more rapidly than that in normal recipients (fractional catabolic rate (FCR) 0.0214 ± 0.0026hr^?1 for autologous and 0.0193 ± 0.0013hr^?1 for isologous HDL in normal (n = 3) and 0.0318 ± 0.0046hr^?1 for autologous and 0.0325 ± 0.0039hr^?1 for isologous HDL in HCHF-fed animals (n = 3). Apolipoprotein A-I from normal or HCHF-fed animals had identical FCR in normal (0.016hr^?1 and 0.0153 ± 0.0006hr^?1) and a similar FCR in HCHF-fed animals (0.026 ± 0.0006hr^?1). Although HCHF-fed animals had a higher FCR for apolipoprotein A-I, the synthesis rate for normal and HCHF-fed animals were similar (0.97 ± 0.12 vs. 0.83 ± 0.21 mg/kg^?1 hr^?1). Apolipoprotein A-II was metabolized differently from A-I. Unlike Apolipoprotein A-I, Apolipoprotein A-II from normal donors was catabolized differently from that from HCHF-fed donors in both groups. The HCHF-fed recipients had much lower FCR of their own A-II (0.0097 ± 0.0006hr^?1) than of normal A-II (0.0333 ± 0.0029hr^?1). In normal monkeys the synthesis rates for A-I and A-II were identical but in HCHF-fed animals the synthesis rate of A-II was lower by an order of magnitude from that of A-I.     

Estrogen-induced increase in uptake of cholesterol-rich very low density lipoproteins in perfused rabbit liver

A nonrecirculating rabbit liver perfusion system was developed to test whether estrogen increases hepatic uptake of radio-iodinated normal and/or cholesterol-rich very low density lipoproteins (VLDL, d < 1.006 g/ml) from cholesterol-fed rabbits. When equal concentrations of VLDL protein from normal rabbits and from cholesterol-fed rabbits were perfused together through the same liver, there was a selectively higher (1.4-fold) uptake of cholesterol-rich VLDL. These particles were rich in apolipoprotein E, and the radioactivity bound to this apolipoprotein was selectively removed by the perfused normal rabbit liver relative to its uptake of apolipoproteins B and C. When livers from estrogen-treated rabbits were perfused under identical conditions as normal livers and with the same lipoproteins, the uptake of cholesterol-rich VLDL was increased by 76%, compared with 21% for normal VLDL.