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The Magnitude of Decrease in Hepatic Very Low Density Lipoprotein Apolipoprotein B Secretion Is Determined by the Extent of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibition in Miniature Pigs¹

Departments of Medicine and Biochemistry and The John P. Robarts Research Institute (J.R.B., L.J.W., D.E.T., S.J.K., M.W.H.), University of Western Ontario, London, Ontario, N6A 5K8 Canada; Department of Medicine (P.H.R.B.), University of Western Australia, Perth, Western Australia, 6001 Australia; and Parke-Davis Pharmaceutical Research (R.S.N.), Warner Lambert Company, Ann Arbor, Michigan 48105

Address all correspondence and requests for reprints to: Murray W. Huff, The John P. Robarts Research Institute, 4–16, University of Western Ontario, 100 Perth Drive, London, Ontario N6A 5K8, Canada. E-mail: mhuff{at}julian.uwo.ca

It has been postulated that the rate of hepatic very low density lipoprotein (VLDL) apolipoprotein (apo) B secretion is dependent upon the activity of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase. To test this hypothesis in vivo, apoB kinetic studies were carried out in miniature pigs before and after 21 days treatment with high-dose (10 mg/kg/day), atorvastatin (A) or simvastatin (S) (n = 5). Pigs were fed a diet containing fat (34% of calories) and cholesterol (400 mg/day; 0.1%). Statin treatment decreased plasma total cholesterol [31 (A) vs. 20% (S)] and low density lipoprotein (LDL) cholesterol concentrations [42 (A) vs. 24% (S)]. Significant reductions in plasma total triglyceride (46%) and VLDL triglyceride (50%) concentrations were only observed with (A). Autologous [¹³¹I]VLDL, [¹²⁵I]LDL, and [³H]leucine were injected simultaneously, and apoB kinetic parameters were determined by triple-isotope multicompartmental analysis using SAAM II. Statin treatment decreased the VLDL apoB pool size [49 (A) vs. 24% (S)] and the hepatic VLDL apoB secretion rate [50 (A) vs. 33% (S)], with no change in the fractional catabolic rate (FCR). LDL apoB pool size decreased [39 (A) vs. 26% (S)], due to reductions in both the total LDL apoB production rate [30 (A) vs. 21% (S)] and LDL direct synthesis [32 (A) vs. 23% (S)]. A significant increase in the LDL apoB FCR (15%) was only seen with (A). Neither plasma VLDL nor LDL lipoprotein compositions were significantly altered. Hepatic HMG-CoA reductase was inhibited to a greater extent with (A), when compared with (S), as evidenced by 1) a greater induction in hepatic mRNA abundances for HMG-CoA reductase (105%) and the LDL receptor (40%) (both P < 0.05); and 2) a greater decrease in hepatic free (9%) and esterified cholesterol (25%) (both P < 0.05). We conclude that both (A) and (S) decrease hepatic VLDL apoB secretion, in vivo, but that the magnitude is determined by the extent of HMG-CoA reductase inhibition.

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