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Mechanism of Action of a 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitor on Apolipoprotein B-100 Kinetics in Visceral Obesity

Departments of Medicine (D.C.C., G.F.W., P.H.R.B., T.A.M., L.J.B.) and Physiology (T.G.R.), University of Western Australia, Western Australian Institute for Medical Research, Royal Perth Hospital, Perth, Western Australia 6847

Address all correspondence and requests for reprints to: Associate Professor G. F. Watts, University Department of Medicine, University of Western Australia, Royal Perth Hospital, G.P.O. Box X2213, Perth, Western Australia, WA 6847. E-mail: . gfwatts{at}cyllene.uwa.edu.au

Abstract

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 [²H₃]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.

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