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 produced a disproportionate decrease in LDL cholesterol compared to LDL apoB, resulting in a significant decrease in the LDL cholesterol/apoB ratio. Electron microscopy revealed that LDL particles were smaller in size and analytical ultracentrifugation demonstrated that colestipol therapy selectively depleted larger, more buoyant LDL particles of Sf degrees 6-7. Thus, colestipol therapy produced LDL that were smaller in size, more dense, and characterized by a decreased cholesterol to protein ratio. To determine whether the altered LDL had different metabolic properties, autologous LDL was isolated from subjects before and during colestipol therapy and their fractional catabolic rates (FCR) were then simultaneously 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. These studies demonstrate that a drug intervention may alter subpopulations of LDL particles in such a way that overall LDL composition 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
SG
Department of Medicine, University of California, San Diego, La Jolla 92093.
Witztum
J L
JL
Carew
T E
TE
Krauss
R W
RW
Lindgren
F T
FT
D000328:Adult; D003084:Colestipol / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008297:Male; D008854:Microscopy, Electron; D008875:Middle Aged; D011073:Polyamines / Q000494:pharmacology*
D008077:Lipoproteins, LDL; D011073:Polyamines; D003084:Colestipol