Central Role of High Density Lipoprotein in Plasma Free Cholesterol Metabolism

Charles C. Schwartz; Z. Reno Vlahcevic; Mones Berman; John G. Meadows; Richard M. Nisman; Leon Swell

doi:10.1172/JCI110582

Central Role of High Density Lipoprotein in Plasma Free Cholesterol Metabolism

Charles C. Schwartz, Z. Reno Vlahcevic, Mones Berman, John G. Meadows, Richard M. Nisman, and Leon Swell

Published July 1, 1982 - More info

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Abstract

This study was designed to provide direct information on the in vivo metabolism in man of free (unesterified) cholesterol in the major lipoprotein classes. Five human subjects were administered one or two (simultaneous) of the following; [2-¹⁴C] mevalonic acid, high density lipoprotein (HDL)-free [¹⁴C] cholesterol, low density lipoprotein (LDL)-free [¹⁴C] cholesterol, and very low density lipoprotein (VLDL)-free [³H]cholesterol. Blood was then obtained at frequent intervals for at least 9 h, and the α(HDL) and β(LDL + VLDL) lipoproteins were quickly separated by heparin-manganese precipitation to prevent ex vivo exchange of free cholesterol. After the administration of [¹⁴C]mevalonic acid the specific activity (disintegrations per minute/micromole) of free cholesterol in the α- and β-lipoproteins increased for 3 h. During this period the α-free cholesterol specific activity was higher than the β specific activity. After administration of VLDL and LDL labeled with free cholesterol, the α-free cholesterol specific activity reached a peak value within 20 min, at which time it was considerably lower than the β-free cholesterol specific activity. When HDL labeled with free cholesterol was administered, a precursor product relationship was observed between the α-free cholesterol (precursor) and β-free cholesterol (product) specific activities.

A multicompartmental model was developed that contained the simplest structure necessary to fit all of the data obtained. The kinetic analysis revealed the presence of extensive exchange (20-85 μmol/min) of free cholesterol between HDL and a tissue pool(s) enriched with newly synthesized free cholesterol. It was found that virtually all (>95%) of the free cholesterol in the β-lipoproteins (LDL+VLDL) cycles directly through HDL. The free cholesterol in LDL appears to behave in the same fashion as the free cholesterol in VLDL.

The results show that there are marked differences in the kinetic behavior of the free cholesterol fractions of α- and β-lipoproteins. There is extensive recycling of free cholesterol between HDL and tissue pools, and between HDL and the β-lipoproteins; this recycling has been quantitated. The findings support the view that in vivo, the free cholesterol in HDL plays a central role in exchange reactions and in the vascular-tissue cholesterol transport system.