Metabolism of human intermediate and very low density lipoprotein subfractions from normal and dysbetalipoproteinemic plasma. In vivo studies in rat.

Subfractions of radioiodinated d less than 1.019 g/ml lipoproteins were isolated by nonequilibrium density gradient ultracentrifugation (DGU) from normal and dysbetalipoproteinemic human plasma and were injected into rats. Size and density (d) of lipoprotein products formed over 8 hours were assessed by gradient gel electrophoresis and equilibrium DGU, respectively. Subfractions containing a subspecies of very low density lipoproteins (VLDL) of particle diameter greater than 350 A were cleared rapidly from the plasma and formed only small amounts of low density lipoproteins (LDL). Fractions containing VLDL subspecies of smaller diameter (300 to 350 A) were cleared much more slowly, and formed greater amounts of a discrete LDL product with the characteristics of human LDL-II (peak particle diameter 255 to 265 A, d = 1.030 to 1.040 g/ml). A similar LDL product was formed from subfractions containing intermediate density lipoproteins (IDL). Cholesterol-enriched subspecies within the smaller, denser portion of the IDL spectrum, however, yielded two additional products. One had size and density characteristic of the major human LDL-I subclass reported previously (265 to 275 A, d = 1.025 to 1.030 g/ml), while the other was yet larger (275 to 285 A) and overlapped normal IDL in size and density. In dysbetalipoproteinemic plasma, the metabolic precursors of the largest product were shifted from the IDL to the small VLDL (beta-VLDL) particle distribution. Since beta-VLDL are known to predispose to accelerated atherosclerosis in dysbetalipoproteinemia, it may be that metabolically homologous cholesterol-enriched IDL subspecies in other subjects have similar atherogenic properties.

Lipolysis products promote the formation of complexes of very-low-density and low-density lipoproteins.

In the course of lipolysis, surface lipid products may accumulate on very-low-density lipoproteins (VLDL). To investigate potential lipoprotein interactions mediated by such products, radiolabeled low-density lipoproteins (LDL) were incubated with VLDL and bovine milk lipoprotein lipase in the presence of limited free fatty acid acceptor. With partial VLDL degradation, association of radiolabeled LDL with VLDL remnants or larger aggregates of VLDL density was demonstrated by gradient gel electrophoresis, agarose chromatography, and density gradient ultracentrifugation. VLDL-LDL complex formation was also observed in incubations with lipid extracts from lipolyzed VLDL or with purified palmitic acid in the absence of lipolysis. Complex formation was inhibited by addition of increasing amounts of albumin as free fatty acid acceptor, but could be detected at molar ratios of free fatty acids/albumin that occur in vivo. Composition analysis of LDL reisolated following incubation with VLDL and lipase under conditions favoring partial complex formation revealed enrichment in glycerides and depletion of cholesterol. We conclude that lipolysis products can promote the formation of stable complexes of LDL and VLDL, and that physical interactions of this nature may play a role in the transfer of lipids and apolipoproteins between lipoprotein particles.

Parathyroid-hormone-induced metabolic alkalosis in dogs.

We examined the effect of parathyroid hormone (PTH), administrated for 24-48 h, on acid-base homeostasis in dogs. Parathyroid extract (PTH), 15 IU/kg/day, given subcutaneously, caused metabolic alkalosis (control vs. experimental; mean +/- SEM): plasma HCO3, 21.3 +/- 0.3 vs. 24.2 +/- 0.5 mEq/l (p less than 0.001); plasma H+, 37.7 +/- 1.1 vs. 35.7 +/- 1.4 nEq/l (p less than 0.05), and net acid excretion, 48.6 +/- 2.0 vs. 65.1 +/- 4.0 mmol/day (p less than 0.01). PTH administered by continuous intravenous infusion had similar effects (control vs. experimental): plasma HCO3, 21.4 +/- 0.4 vs. 23.6 +/- 0.7 mEq/l (p less than 0.001) and net acid excretion, 54.0 +/- 3.5 vs. 68.3 +/- 5.7 mmol/day (p less than 0.05). PTH, 8 IU/kg/day, had qualitatively similar but quantitatively less profound consequences. Bicarbonaturia was not observed in any group. The effects of PTH were similar in adrenalectomized dogs maintained on hormone replacement. Indomethacin (150 mg/day) prevented the renal effects of PTH so that no increase in net acid secretion occurred. However, metabolic alkalosis still developed: control vs. experimental plasma HCO3, 21.8 +/- 0.5 vs. 23.9 +/- 0.5 mEq/l (p less than 0.001). Dichloromethanediphosphonate blunted both the renal and nonrenal effects of PTH, such that hypercalcemia, metabolic alkalosis and increased net acid excretion were quantitatively less and delayed in onset. In summary, PTH administration for 24-48 h causes metabolic alkalosis in dogs, the result of renal and nonrenal mechanisms.