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J. Biol. Chem., Vol. 279, Issue 27, 28106-28112, July 2, 2004

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The Hepatitis B Virus X Protein Inhibits Secretion of Apolipoprotein B by Enhancing the Expression of N-Acetylglucosaminyltransferase III^*

Sung-Koo Kang, Tae-Wook Chung, Ji-Young Lee, Young-Choon Lee, Richard E. Morton¶, and Cheorl-Ho Kim||

From the National Research Laboratory for Glycobiology, and Department of Biochemistry and Molecular Biology, College of Oriental Medicine, Dongguk University, Kyungju, Kyungbuk 780-714, Korea, Faculty of Biotechnology, Dong-A University, Saha-gu, Busan 604-714, Korea, and ^¶Department of Cell Biology, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195

The X protein of hepatitis B virus (HBx) plays a major role on hepatocellular carcinoma (HCC). Apolipoprotein B (apoB) in the liver is an important glycoprotein for transportation of very low density lipoproteins and low density lipoproteins. Although lipid accumulation in the liver is known as one of the factors for the HCC, the relationship between HBx and apoB during the HCC development is poorly understood. To better understand the biological significance of HBx in HCC, liver Chang cells that specifically express HBx were established and characterized. In this study we demonstrate that overexpression of HBx significantly up-regulates the expression of UDP-N-acetylglucosamine:-D-mannoside-1,4-N-acetylglucosaminyltransferase-III (GnT-III), an enzyme that functions as a bisecting-N-acetylglucosamine (GlcNAc) transferase in apoB, and increases GnT-III promoter activity in a chloramphenicol acetyltransferase assay. GnT-III expression levels of HBx-transfected cells appeared to be higher than that of hepatocarcinoma cells as well as GnT-III-transfected cells, indicating that HBx may has a strong GnT-III promotor-enhancing activity. Intracellular levels of apoBs, which contained the increased bisecting GlcNAc, were accumulated in HBx-transfected liver cells. These cells as well as GnT-III-transfected liver cells revealed the inhibition of apoB secretion and the increased accumulation of intracellular triglyceride and cholesterol compared with vector-transfected cells. Moreover, overexpression of GnT-III and HBx in liver cells was shown to down-regulate the transcriptional level of microsomal triglyceride transfer protein, which regulates the assembly and secretion of apoB. Therefore, our study strongly suggested that the HBx increase in intracellular accumulation of aberrantly glycosylated apoB resulted in inhibition of secretion of apoB as well as intracellular lipid accumulation by elevating the expression of GnT-III.

Received for publication, March 22, 2004 , and in revised form, April 19, 2004.

^* This work was supported by National Research Laboratory Program, Ministry of Science and Technology, South Korea Grant M10203000024-02J0000-01300 (to C.-H. K.). 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: NRLG and Dept. of Biochemistry and Molecular Biology, Dongguk University, Sukjang-Dong 707, Kyungju City, Kyungbuk 780-714, Korea. Tel.: 82-54-770-2663; Fax: 82-54-770-2281; E-mail: chkimbio{at}dongguk.ac.kr.

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