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J. Biol. Chem., Vol. 279, Issue 27, 28662-28669, July 2, 2004

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The Peroxisome Proliferator-activated Receptor (PPAR) Agonist Ciprofibrate Inhibits Apolipoprotein B mRNA Editing in Low Density Lipoprotein Receptor-deficient Mice

EFFECTS ON PLASMA LIPOPROTEINS AND THE DEVELOPMENT OF ATHEROSCLEROTIC LESIONS^*

Tao Fu, Debnath Mukhopadhyay, Nicholas O. Davidson, and Jayme Borensztajn¶

From the Department of Pathology, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611 and the Department of Internal Medicine, Washington University, St. Louis, Missouri 63110

Low density lipoprotein receptor (LDLR)-deficient mice fed a chow diet have a mild hypercholesterolemia caused by the abnormal accumulation in the plasma of apolipoprotein B (apoB)-100- and apoB-48-carrying intermediate density lipoproteins (IDL) and low density lipoproteins (LDL). Treatment of LDLR-deficient mice with ciprofibrate caused a marked decrease in plasma apoB-48-carrying IDL and LDL but at the same time caused a large accumulation of triglyceride-depleted apoB-100-carrying IDL and LDL, resulting in a significant increase in plasma cholesterol levels. These plasma lipoprotein changes were associated with an increase in the hepatic secretion of apoB-100-carrying very low density lipoproteins (VLDL) and a decrease in the secretion of apoB-48-carrying VLDL, accompanied by a significant decrease in hepatic apoB mRNA editing. Hepatic apobec-1 complementation factor mRNA and protein abundance were significantly decreased, whereas apobec-1 mRNA and protein abundance remained unchanged. No changes in apoB mRNA editing occurred in the intestine of the treated animals. After 150 days of treatment with ciprofibrate, consistent with the increased plasma accumulation of apoB-100-carrying IDL and LDL, the LDLR-deficient mice displayed severe atherosclerotic lesions in the aorta. These findings demonstrate that ciprofibrate treatment decreases hepatic apoB mRNA editing and alters the pattern of hepatic lipoprotein secretion toward apoB-100-associated VLDL, changes that in turn lead to increased atherosclerosis.

Received for publication, March 24, 2004 , and in revised form, April 26, 2004.

^* This work was supported in part by a Merit Review Grant from the Department of Veterans Affairs (to J. B.), by the Sidney and Bess Eisenberg Memorial Fund (to J. B.), by Grants HL-38180 and DK-56260 from the National Institutes of Health (to N. O. D.), and by Digestive Disease Research Center Core Grant DK-52574 from the National Institutes of Health (to N. O. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Pathology, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 60611. Tel.: 312-503-8590; Fax: 312-503-8240; E-mail: jbb{at}northwestern.edu.

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