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 cholesterol:protein 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 cholestyramine-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 cholesterol:protein 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 125I or 131I and simultaneously injected them into control and cholestyramine-treated guinea pigs. In 27/29 animals studied, the FCR of the CH-LDL was slower than that of C-LDL, demonstrating 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 increased 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-LDL. 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.