Mechanism of action of a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor on apolipoprotein B-100 kinetics in visceral obesity.
We examined the effect of atorvastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, on the kinetics of apolipoprotein B-100 (apoB) metabolism in 25 viscerally obese men in a placebo-controlled study. Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured using an iv bolus injection of [(2)H(3)]leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived by using a multicompartmental model (SAAM-II). Compared with the placebo group, atorvastatin treatment resulted in significant (P < 0.001) decreases in total cholesterol (-34%), triglyceride (-19%), LDL cholesterol (-42%), total apoB (-39%), and lathosterol (-86%); VLDL-apoB, IDL-apoB, and LDL-apoB pool sizes also fell significantly (P < 0.002) by -27%, -22%, and -41%, respectively. This was associated with an increase in the fractional catabolic rates of VLDL-apoB (+58%, P = 0.019), IDL-apoB (+40%, P = 0.049), and LDL-apoB (+111%, P = 0.001). However, atorvastatin did not significantly alter the production and conversion rates of apoB in all lipoproteins. We conclude that in obese subjects, atorvastatin decreases the plasma concentration of all apoB-containing lipoproteins chiefly by increasing their catabolism and not by decreasing their production or secretion. This may be owing to up-regulation of hepatic receptors as a consequence of inhibition of cholesterogenesis.
Chan
Dick C
DC
Department of Medicine, University of Western Australia, Western Australian Institute for Medical Research, Royal Perth Hospital, Perth, Western Australia 6847.
Watts
Gerald F
GF
Barrett
P Hugh R
PH
Mori
Trevor A
TA
Beilin
Lawrence J
LJ
Redgrave
Trevor G
TG
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B / Q000037:antagonists & inhibitors / Q000097:blood* / Q000378:metabolism; D000069059:Atorvastatin; D004311:Double-Blind Method; D006538:Heptanoic Acids / Q000627:therapeutic use*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007700:Kinetics; D008074:Lipoproteins / Q000378:metabolism; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000097:blood* / Q000188:drug therapy* / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D014781:Viscera
D000924:Anticholesteremic Agents; D053299:Apolipoprotein B-100; D001055:Apolipoproteins B; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008074:Lipoproteins; D053419:Lipoproteins, IDL; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011758:Pyrroles; D000069059:Atorvastatin