Effects of lovastatin therapy on guinea pig low density lipoprotein composition and metabolism

Lovastatin therapy is known to induce hepatic low density lipoprotein (LDL) receptor mRNA and LDL receptor activity. Yet, in studies in humans and animals it has been difficult to demonstrate an enhancement of the plasma fractional catabolic rate (FCR) of an injected LDL tracer during lovastatin therapy. One explanation may be that the composition of the LDL tracer may also change during therapy, independently affecting LDL clearance. To test this possibility we fed guinea pigs lovastatin, which led to a decrease in their plasma LDL cholesterol levels. Composition studies showed that LDL isolated from lovastatin-treated guinea pigs was slightly cholesterol-depleted and triglyceride-enriched when compared to LDL isolated from control animals. Several independent lines of investigation documented that a substantial increase in hepatic LDL receptor activity occurred in response to the lovastatin treatment. Consistent with this, when a single LDL tracer was injected into control and lovastatin-treated guinea pigs, the FCR was always more rapid in the lovastatin-treated animals. However, when LDL isolated from lovastatin-treated animals (L-LDL) was simultaneously injected intravenously with LDL isolated from control animals (C-LDL) the FCR of the C-LDL was always more rapid than that of the L-LDL. When one compared the FCR of C-LDL determined in control animals with the FCR of L-LDL determined in lovastatin animals there was no difference. Possible explanations for these paradoxical findings are discussed.