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J. Biol. Chem., Vol. 281, Issue 40, 29797-29806, October 6, 2006

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Fucosylation of N-Glycans Regulates the Secretion of Hepatic Glycoproteins into Bile Ducts^*

Tsutomu Nakagawa, Naofumi Uozumi^||, Miyako Nakano, Yoko Mizuno-Horikawa, Noriko Okuyama, Tomohiko Taguchi, Jianguo Gu, Akihiro Kondo, Naoyuki Taniguchi^¶, and Eiji Miyoshi^||1

From the Departments of Biochemistry, and Glycotherapeutics, Osaka University Graduate School of Medicine, the ^¶Department of Disease Glycomics, Research Institute for Microbial Diseases, Osaka University, 565-0871 Osaka, Japan and ^||Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, 332-0012 Saitama, Japan

Fucosylated -fetoprotein (AFP) is a highly specific tumor marker for hepatocellular carcinoma (HCC). However, the molecular mechanism by which serum level of fucosylated AFP increases in patients with HCC remains largely unknown. Here, we report that the fucosylation of glycoproteins could be a possible signal for secretion into bile ducts in the liver. We compared oligosaccharide structures on glycoproteins in human bile with those in serum by several types of lectin blot analyses. Enhanced binding of biliary glycoproteins to lectins that recognize a fucose residue was observed over a wide range of molecular weights compared with serum glycoproteins. A structural analysis of oligosaccharides by two-dimensional mapping high performance liquid chromatography and matrix-assisted laser desorption ionization time-of flight mass spectrometry confirmed the increases in the fucosylation of biliary glycoproteins. Purification followed by structural analysis on 1-antitrypsin, 1-acid glycoprotein and haptoglobin, which are synthesized in the liver, showed higher fucosylation in bile than in serum. To find direct evidence for fucosylation and sorting signal into bile ducts, we used 1–6 fucosyltransferase (Fut8)-deficient mice because fucosylation of glycoproteins produced in mouse liver was mainly an 1–6 linkage. Interestingly, the levels of 1-antitrypsin and 1-acid glycoprotein were quite low in bile of Fut8-deficient mice as compared with wild-type mice. An immunohistochemical study showed dramatic changes in the localization of these glycoproteins in the liver of Fut8-deficient mice. Taken together, these results suggest that fucosylation is a possible signal for the secretion of glycoproteins into bile ducts in the liver. A disruption in this system might involve an increase in fucosylated AFP in the serum of patients with HCC.

Received for publication, June 14, 2006

^* This work was supported in part by Grants-in-aid for Scientific Research (S) (13854010) and (C) (16590245), the Special Coordination Funds for Promoting Science and Technology, and the 21st Century Center of Excellence Program from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. A part of this work was supported by Japan Science and Technology Agency and the New Energy and Industrial Technology Development Organization as part of a research and development project related to medical glycology. 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed: Dept. of Biochemistry, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, 565-0871 Osaka, Japan. Tel.: 81-6-6879-3421; Fax: 81-6-6879-3429; E-mail: miyoshi34{at}biochem.med.osaka-u.ac.jp.

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