Colestipol-induced changes in LDL composition and metabolism. II. Studies in humans.

We investigated the effect of the bile acid sequestrant, colestipol hydrochloride, on the composition and metabolism of human low density lipoprotein (LDL). Colestipol treatment pro- duced a disproportionate decrease in LDL cholesterol compared to LDL apoB, resulting in a significant decrease in the LDL choles- terol/apoB ratio. Electron microscopy revealed that LDL particles were smaller in size and analytical ultracentrifugation demon- strated that colestipol therapy selectively depleted larger, more buoyant LDL particles of Sfo 6-7. Thus, colestipol therapy produced LDL that were smaller in size, more dense, and charac- terized by a decreased cholesterol to protein ratio. To determine whether the altered LDL had different metabolic properties, auto- logous LDL was isolated from subjects before and during colestipol therapy and their fractional catabolic rates (FCR) were then simul- taneously determined in the same patient while on therapy. Eight LDL turnover studies comparing the catabolism of LDL isolated during therapy (Rx-LDL) and LDL isolated off therapy (Con- LDL) were performed in six subjects. All subjects responded to colestipol treatment, with an average 29% fall in LDL cholesterol. In four of six subjects, and in six of eight studies, the FCR of Rx- LDL was substantially slower than that of Con-LDL. I These studies demonstrate that a drug intervention may alter subpopu- lations of LDL particles in such a way that overall LDL compo- sition is changed. This alteration may independently affect the intrinsic metabolic behavior of the LDL. We suggest that such drug- (or dietary-) induced changes in LDL composition need to be considered in kinetic studies designed to assess the overall impact of the perturbation being studied.-Young, S. G., J. L. Witztum, T. E. Carew, R. M. Krauss, and F. T. Lindgren. Colestipol-induced changes in LDL composition and metabolism. 11. Studies in humans. J. Lipid Res. 1989. 30: 225-238. a greater decrease in levels of LDL-cholesterol than levels of LDL-apoB. In a recent study (8) we showed that bile sequsstrant resins effectively lowered LDL levels in guinea pigs, and that the LDL isolated from cholestyramine-treated guinea pigs was altered in a manner similar to that noted in treated humans. We also showed that the altered LDL had different meta- bolic properties compared to control-LDL, isolated in the absence of drug treatment (8). In this report, we document that the bile sequestrant colestipol hydrochloride signifi- cantly alters the composition, size, and density of human LDL, and we demonstrate that LDL isolated during bile sequestrant therapy has different metabolic properties than control-LDL. Potential implications of these observations are discussed.