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Rosuvastatin Enhances the Catabolism of LDL apoB-100 in Subjects with Combined Hyperlipidemia in a Dose Dependent Manner

  • Original Article
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Lipids

Abstract

Dose-associated effects of rosuvastatin on the metabolism of apolipoprotein (apo) B-100 in triacylglycerol rich lipoprotein (TRL, d < 1.019 g/ml) and low density lipoprotein (LDL) and of apoA-I in high density lipoprotein (HDL) were assessed in subjects with combined hyperlipidemia. Our primary hypothesis was that maximal dose rosuvastatin would decrease the apoB-100 production rate (PR), as well as increase apoB-100 fractional catabolic rate (FCR). Eight subjects received placebo, rosuvastatin 5 mg/day, and rosuvastatin 40 mg/day for 8 weeks each in sequential order. The kinetics of apoB-100 in TRL and LDL and apoA-I in HDL were determined at the end of each phase using stable isotope methodology, gas chromatography-mass spectrometry, and multicompartmental modeling. Rosuvastatin at 5 and 40 mg/day decreased LDL cholesterol by 44 and 54 % (both P < 0.0001), triacylglycerol by 14 % (ns) and 35 % (P < 0.01), apoB by 30 and 36 % (both P < 0.0001), respectively, and had no significant effects on HDL cholesterol or apoA-I levels. Significant decreases in plasma markers of cholesterol synthesis and increases in cholesterol absorption markers were observed. Rosuvastatin 5 and 40 mg/day increased TRL apoB-100 FCR by 36 and 46 % (both ns) and LDL apoB-100 by 63 and 102 % (both P < 0.05), respectively. HDL apoA-I PR increased with low dose rosuvastatin (12 %, P < 0.05) but not with maximal dose rosuvastatin. Neither rosuvastatin dose altered apoB-100 PR or HDL apoA-I FCR. Our data indicate that maximal dose rosuvastatin treatment in subjects with combined hyperlipidemia resulted in significant increases in the catabolism of LDL apoB-100, with no significant effects on apoB-100 production or HDL apoA-I kinetics.

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Abbreviations

ABCA1:

ATP-binding cassette A1

Apo:

Apolipoprotein

BMI:

Body mass index

CETP:

Cholesteryl ester transfer protein

CHD:

Coronary heart disease

d :

Density

EDTA:

Ethylenediaminetetraacetic acid

FCR:

Fractional catabolic rate

GC–MS:

Gas chromatography-mass spectrometry

HMG-CoA:

3-Hydroxy-3-methylglutaryl-CoA

IDL:

Intermediate density lipoprotein

PR:

Production rate

PS:

Pool size

R5:

Rosuvastatin low dose (5 mg/day)

R40:

Rosuvastatin maximal dose (40 mg/day)

TC:

Total cholesterol

TAG:

Triacylglycerol

TRL:

Triacylglycerol rich lipoprotein

VLDL:

Very low density lipoprotein

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Acknowledgments

The authors thank the staff of the Clinical Interaction Network of the Atlanta CTSI for their support and dedication in the conduct of the study. The authors are grateful to Dr. James Otvos and the technical staff at LipoScience for their assistance with the NMR analysis and to Dr. Eliana Polisecki and her staff at Boston Heart Diagnostics for their assistance with the plasma sterol analysis. The technical assistance of Wing-Yee Wan, Robert Matera, and Dr. Pimjai Anthanont is much appreciated. This research was supported by an investigator-initiated grant from AstraZeneca to Drs. N.-A. Le and W. V. Brown. Additional support was provided by PHS grant UL1 RR025008 from the National Institutes of Health (N.-A.L., W.V.B.), by US Department of Agriculture Research Service Contract 53-3K-06 (E.J.S.), and by Project Grant P50 HL083813-01 from the National Institutes of Health (E.J.S.). The contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health or the US Department of Agriculture. P.H.R.B. is a fellow of the National Health and Medical Research Council of Australia; E.M.M.O., a postdoctoral research fellow of the National Health and Medical Research Council of Australia; and N.T., a postdoctoral research fellow from Siriraj Hospital, Mahidol University, Thailand.

Conflict of interest

This study was funded in part by AstraZeneca (N.-A.L. and W.V.B.). During the past five years, support for ancillary research related to this study has been provided by AstraZeneca (E.J.S. and M.R.D.). None of the authors owns stock or warrants in this company.

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Authors and Affiliations

  1. Atlanta Veterans Affairs Medical Center, Decatur, GA, USA

    Ngoc-Anh Le & W. Virgil Brown

  2. Emory University School of Medicine, Atlanta, GA, 30305, USA

    Ngoc-Anh Le & W. Virgil Brown

  3. Lipid Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA

    Margaret R. Diffenderfer, Nuntakorn Thongtang, Esther M. M. Ooi, Katalin V. Horvath, Bela F. Asztalos & Ernst J. Schaefer

  4. Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand

    Nuntakorn Thongtang

  5. Metabolic Research Centre, School of Medicine and Pharmacology, Royal Perth Hospital, University of Western Australia, Perth, WA, Australia

    Esther M. M. Ooi & P. Hugh R. Barrett

  6. Mass Spectrometry Unit, Jean Mayer USDA Human Nutrition Research Center on Aging, Tufts University, Boston, MA, USA

    Gregory G. Dolnikowski

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  1. Ngoc-Anh Le
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  8. Bela F. Asztalos
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Correspondence to W. Virgil Brown.

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Clinical Trial Registration Number: none assigned (study prior to 2005).

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Le, NA., Diffenderfer, M.R., Thongtang, N. et al. Rosuvastatin Enhances the Catabolism of LDL apoB-100 in Subjects with Combined Hyperlipidemia in a Dose Dependent Manner. Lipids 50, 447–458 (2015). https://doi.org/10.1007/s11745-015-4005-0

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