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Journal of Lipid Research, Vol. 46, 2735-2744, December 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Treatment with high-dose simvastatin reduces secretion of apolipoprotein B-lipoproteins in patients with diabetic dyslipidemia

Merle Myerson^*, Colleen Ngai^*, Jeffrey Jones^*, Steve Holleran, Rajasekhar Ramakrishnan, Lars Berglund^* and Henry N. Ginsberg^1,*

^* Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032
Department of Pediatrics, Columbia University College of Physicians and Surgeons, New York, NY 10032

Published, JLR Papers in Press, September 14, 2005. DOI 10.1194/jlr.M500335-JLR200

¹ To whom correspondence should be addressed. e-mail: hng1{at}columbia.edu

HMG-CoA reductase inhibitors (statins) are effective lipid-altering drugs for the treatment of dyslipidemia in patients with type 2 diabetes mellitus. We conducted a randomized, double-blind, placebo-controlled, crossover design trial to determine the effects of simvastatin, 80 mg/day, on plasma lipid and lipoprotein levels and on the metabolism of apolipoprotein B (apoB) in VLDL, intermediate density lipoprotein (IDL), and LDL and of triglycerides (TGs) in VLDL. Simvastatin therapy decreased TG, cholesterol, and apoB significantly in VLDL, IDL, and LDL. These effects were associated with reduced production of LDL-apoB, mainly as a result of reduced secretion of apoB-lipoproteins directly into the LDL density range. Statin therapy also reduced hepatic production of VLDL-TG. There were no effects of simvastatin on the fractional catabolic rates of VLDL-apoB or -TG or LDL-apoB. The basis for decreased VLDL-TG secretion during simvastatin treatment is not clear, but recent studies suggest that statins may activate peroxisomal proliferator-activated receptor (PPAR).

Activation of PPAR could lead to increased hepatic oxidation of fatty acids and less synthesis of TG for VLDL assembly.

Supplementary key words very low density lipoproteins • low density lipoproteins • triglycerides • 3-hydroxy-3-methyl glutaryl coenzyme A reductase inhibitors • statins • diabetes mellitus • hypertriglyceridemia

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