Effects of simvastatin on apoB metabolism and LDL subfraction distribution.
Seven moderately hypercholesterolemic subjects were studied before and after 10 weeks of simvastatin therapy (20 mg/day). Therapy reduced low density lipoprotein (LDL) cholesterol by 39% (p < 0.001), whereas high density lipoprotein and very low density lipoprotein (VLDL) cholesterol were unchanged. Apolipoprotein (apo) B-containing lipoproteins were divided into VLDL1 (Sf 60-400), VLDL2 (Sf 20-60), intermediate density lipoprotein (IDL) (Sf 12-20), and LDL (Sf 0-12), and metabolic changes were sought in dual-tracer VLDL1 and VLDL2 turnover studies. VLDL1 apoB pool size was unaltered by therapy, as were its rates of synthesis, catabolism, and delipidation to VLDL2. Similarly, the VLDL2 apoB pool size was unchanged, but its metabolic fate was altered. The IDL pool size fell significantly (27%, p < 0.01) due entirely to an increased fractional catabolism of the lipoprotein. In our subjects, the circulating mass of LDL apoB decreased (49%, p < 0.01) primarily due to a reduction in its synthesis. Before therapy, 30% of the apoB entering the delipidation cascade in these hyperlipidemic subjects was converted to LDL. On therapy the input remained the same, but direct catabolism from VLDL2 and IDL was increased (p < 0.05), and as a result only 16% eventually appeared in LDL. These kinetic changes were associated with a fall in particle cholesteryl ester content throughout the delipidation cascade. We also observed a link between LDL kinetics and its subfraction distribution. Simvastatin influences the metabolism of LDL, IDL, and VLDL2 but not VLDL1.
Gaw
A
A
Institute of Biochemistry, Glasgow Royal Infirmary, UK.
Packard
C J
CJ
Murray
E F
EF
Lindsay
G M
GM
Griffin
B A
BA
Caslake
M J
MJ
Vallance
B D
BD
Lorimer
A R
AR
Shepherd
J
J
D000328:Adult; D001055:Apolipoproteins B / Q000378:metabolism*; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL / Q000032:analysis / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008148:Lovastatin / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008875:Middle Aged; D019821:Simvastatin
D001055:Apolipoproteins B; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D008148:Lovastatin; D019821:Simvastatin