Cholestyramine-induced changes in low density lipoprotein composition and metabolism. I. Studies in the guinea pig.

In previous animal studies, bile acid sequestrant resins have been shown to increase the fractional catabolic rate (FCR) of a low density lipoprotein (LDL) tracer isolated from a normal donor animal and to increase hepatic LDL- receptor activity. In addition, in man, these resins are known to alter LDL composition such that low density lipoproteins are smaller, more dense, and have a decreased cholestero1:pro- tein ratio. To determine whether metabolic consequences resulted from these changes in LDL composition, we fed cholestyramine chow (2% resin by weight) to guinea pigs, which lowered LDL cholesterol levels by 55 % . LDL was isolated from control donors (C-LDL) and from cholestyra- mine-treated donors (CH-LDL). Compared to the C-LDL, the CH-LDL were smaller in size, depleted of cholesteryl ester and phospholipid, and had a marked decrease in their cholesterohprotein ratio. To determine whether the clearance of the altered CH-LDL was different from that of C-LDL, we labeled the two LDL preparations with '''1 or I3'I and simultaneously injected them into control and cholestyra- mine-treated guinea pigs. In 27/29 animals studied, the FCR of the CH-LDL was slower than that of C-LDL, demonstrat- ing that the compositional changes alter the metabolism of CH-LDL. When C-LDL was used as the sole tracer in both control and treated animals, cholestyramine treatment in- creased the FCR by 41%; when CH-LDL was used as sole tracer, the increase in FCR on treatment was only 26 % . This suggested that C-LDL was cleared more rapidly by the LDL- receptor pathway than was CH-LDL. Further support for this idea came from observations that C-LDL was degraded more readily by cultured fibroblasts and that nonenzymatic glucosylation abolished the difference in FCR between C- LDL and CH-LDLI These studies show that the effects of bile sequestration are complex and that the compositional changes produced have profound metabolic consequences. The implications of these observations for interpretation of LDL turnover studies are discussed.-Witztum, J. L., S. G. Young, R. L. Elam, T. E. Carew, and M. Fisher. Cholestyra- mine-induced changes in low density lipoprotein composition and metabolism. I. Studies in the guinea pig. 1. Lipid Res. 1985. 26: 92-103. Bile acid sequestrant resins are widely used in the therapy of hypercholesterolemia as they specifically lower plasma concentrations of low density lipoproteins (LDL) (1-3). In previous animal studies, they have been shown to increase the fractional catabolic rate (FCR) of normal LDL and to increase hepatic LDL-receptor activity (4-8). In addition to these effects we have pre- viously shown that these resins, when administered to human subjects, produce marked alterations in the composition of LDL (1,2) (S. G. Young, J. L. Witztum, T. E. Carew, R. M. Krauss, and E T. Lindgren, unpub- lished results). In particular, the low density lipopro- teins are more dense, smaller in size, and have a de- creased cholestero1:protein ratio. The mechanisms under- lying these compositional changes are unknown, nor is it known whether such changes in composition have metabolic consequences. To answer these questions, we developed an animal model in which bile sequestration would produce similar changes in LDL composition, and then determined whether metabolic consequences resulted from such changes. In this report we show that bile acid sequestrant resins effectively lower LDL levels in guinea pigs, and produce many of the alterations in LDL composition noted in humans. We also show that such altered LDL have a different FCR than LDL isolated from normal animals.