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J. Biol. Chem., Vol. 280, Issue 18, 18336-18340, May 6, 2005

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Phospholipid Transfer Protein Deficiency Impairs Apolipoprotein-B Secretion from Hepatocytes by Stimulating a Proteolytic Pathway through a Relative Deficiency of Vitamin E and an Increase in Intracellular Oxidants^*

Xian-Cheng Jiang, Zhiqiang Li, Ruijie Liu, Xiao Ping Yang, Meihui Pan¶, Laurent Lagrost||, Edward A. Fisher¶, and Kevin Jon Williams**

From the State University of New York Downstate Medical Center, Brooklyn, New York 11203, the ^¶New York University School of Medicine, New York, New York 10016, ^|| INSERM U498, 21079 Dijon, France, and the ^**Dorrance H. Hamilton Research Laboratories, Division of Endocrinology, Diabetes and Metabolic Diseases, Department of Medicine, Jefferson Medical College of Thomas Jefferson University, Philadelphia, Pennsylvania 19107

Genetic deficiency of the plasma phospholipid transfer protein (PLTP) in mice unexpectedly causes a substantial impairment in liver secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins. To explore the mechanism, we examined the three known pathways for hepatic apoB secretory control, namely endoplasmic reticulum (ER)/proteasome-associated degradation (ERAD), post-ER pre-secretory proteolysis (PERPP), and receptor-mediated degradation, also known as re-uptake. First, we found that ERAD and cell surface re-uptake were not active in PLTP-null hepatocytes. Moreover, ER-to-Golgi blockade by brefeldin A, which enhances ERAD, equalized total apoB recovery from PLTP-null and wild-type cells, indicating that the relevant process occurs post-ER. Second, because PERPP can be stimulated by intracellular reactive oxygen species (ROS), we examined hepatic redox status. Although we found previously that PLTP-null mice exhibit elevated plasma concentrations of vitamin E, a lipid anti-oxidant, we now discovered that their livers contain significantly less vitamin E and significantly more lipid peroxides than do livers of wild-type mice. Third, to establish a causal connection, the addition of vitamin E or treatment with an inhibitor of intracellular iron-dependent peroxidation, desferrioxamine, abolished the elevation in cellular ROS as well as the defect in apoB secretion from PLTP-null hepatocytes. Overall, we conclude that PLTP deficiency decreases liver vitamin E content, increases hepatic oxidant tone, and substantially enhances ROS-dependent destruction of newly synthesized apoB via a post-ER process. These findings are likely to be broadly relevant to hepatic apoB secretory control in vivo.

Received for publication, January 1, 2005 , and in revised form, February 22, 2005.

^* This work was supported by National Institutes of Health Grants HL-64735, HL-69817 (both to X.-C. J.), HL58541 (to E. A. F.), and HL56984 (to K. J. W.), and American Diabetes Association Grant RA-81 (to K. J. W.). A preliminary report on this work was presented at the American Heart Association Scientific Sessions, November 17-20, 2002 in Chicago, IL. 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 may be addressed: Downstate Medical Center, 450 Clarkson Ave. Rm. 2-31, Brooklyn, NY 11203. Tel.: 718-270-6701; Fax: 718-270-3732; E-mail: Xian-Cheng_Jiang{at}downstate.edu.

To whom correspondence may be addressed: Dept. of Medicine, Thomas Jefferson University, 1020 Locust St., Suite 348, Philadelphia, PA 19107. Tel.: 215-503-1272; Fax: 215-923-7932; E-mail: K_Williams{at}mail.jci.tju.edu.

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