Ectopic expression of  1,6 fucosyltransferase in mice causes steatosis in the liver and kidney accompanied by a modification of lysosomal acid lipase

Wang, Wenge; Li, Wei; Ikeda, Yoshitaka; Miyagawa, Jun‐ichiro; Taniguchi, Masako; Miyoshi, Eiji; Sheng, Yin; Ekuni, Atsuko; Ko, Jeong Heon; Yamamoto, Yorihiro; Sugimoto, Tomoyuki; Yamashita, Shizuya; Matsuzawa, Yūji; Grabowski, Gregory A.; Honke, Koichi; Taniguchi, Naoyuki

doi:10.1093/glycob/11.2.165

Cited by 33 publications

(26 citation statements)

References 48 publications

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“…␣1,6-Fucosylation regulates E-cadherin-mediated cell adhesion (13), ␣3␤1 integrin function (47), antibody-dependent cellular cytotoxicity of IgG (38,39), liver lysosomal acid lipase activity (43), transforming growth factor-␤1 signaling (45), EGF receptor-mediated intracellular signaling (44), and protein secretion from the liver into the bile duct (33). Given those changes in protein properties by ␣1,6-fucosylation, the increase in ␣1,6-fucosylation may affect a variety of glycoprotein properties in type 2 DM.…”

Section: Discussionmentioning

confidence: 99%

Analysis ofN-glycan in serum glycoproteins fromdb/dbmice and humans with type 2 diabetes

Itoh¹,

Sakaue²,

Nakagawa³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Glycosylation has an important role in regulating properties of proteins and is associated with many diseases. To examine the alteration of serum N-glycans in type 2 diabetes, we used the db/db mouse model. Serum N-glycans were fluorescence labeled and applied to HPLC. There were reproducible differences in N-glycan profiles between the db/db mouse model and the db/+ control. The structures of the oligosaccharides, which had changed in their amounts, were analyzed by a two-dimensional mapping method, matrix-assisted laser desorption ionization-time-of-flight mass spectrometry, and exoglycosidase digestion. Those analyses revealed an increase in the N-glycans possessing α1,6-fucose in the serum of db/db mice. The level of α1,6-fucosyltransferase mRNA was increased in the liver of the db/db mice. The ratio of a biantennary N-glycan with α1,6-fucose to that without α1,6-fucose in the liver tissue of the db/db mouse was increased relative to the db/+ control. Next, we analyzed the serum N-glycan profile in human subjects with type 2 diabetes and found an increased amount of a biantennary N-glycan that had an α1,6-fucose with a bisecting N-acetylglucosamine. In conclusion, the increase in α1,6-fucosylation is a striking change in the serum N-glycans of the db/db mice, whereas the change in the fucosylation in humans with type 2 diabetes was small, albeit statistically significant. It is likely that the change is caused, at least partially, by the increase in the α1,6-fucosyltransferase mRNA level in the liver. The increased α1,6-fucosylation may affect protein properties associated with the pathophysiology of type 2 diabetes.

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Section: Discussionmentioning

confidence: 99%

Analysis ofN-glycan in serum glycoproteins fromdb/dbmice and humans with type 2 diabetes

Itoh¹,

Sakaue²,

Nakagawa³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Previous studies have shown that glycosyltransferase transgenic mice develop fatty liver due to the accumulation of lipoproteins in their hepatocytes (23,24). However, GnT-V Tg mice did not show fatty liver phenotypes under normal conditions.…”

Section: The Role Of Gnt-v In the Development Of Steato-hepatitismentioning

confidence: 93%

Physiological roles of N-acetylglucosaminyltransferase V (GnT-V) in mice

Miyoshi¹,

Terao²,

Kamada³

2012

BMB Reports

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“…Lacking the core fucose on these receptors leads to a marked reductions in ligand binding ability and downstream signaling. Furthermore, the increase in core fucosylation on E-cadherin has been shown to strengthen cell-cell adhesion (10).Both transgenic and knockout mouse models have been generated to study the physiological role of FUT8 (7,11,12). Ectopic expression of FUT8 in mice results in an accumulation of lipid droplets in hepatocytes and proximal renal tubular cells.…”

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confidence: 99%

Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer

Chen

Jan

Juan

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

227

199

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The up-regulation of fucosyltransferase 8 (FUT8), the only enzyme catalyzing α1,6-fucosylation in mammals, has been observed in several malignant cancers including liver, ovarian, thyroid, and colorectal cancers. However, the pathological role and the regulatory mechanism of FUT8 in cancers remain largely unknown. In the current study, we report that the expression of FUT8 is up-regulated in nonsmall cell lung cancer (NSCLC) and correlates with tumor metastasis, disease recurrence, and poor survival in patients with NSCLC. Knocking down FUT8 in aggressive lung cancer cell lines significantly inhibits their malignant behaviors including in vitro invasion and cell proliferation, as well as in vivo metastasis and tumor growth. The results of glycoproteomic and microarray analyses show that FUT8 globally modifies surface antigens, receptors, and adhesion molecules and is involved in the regulation of dozens of genes associated with malignancy, suggesting that FUT8 contributes to tumor progression through multiple mechanisms. Moreover, we show that FUT8 is up-regulated during epithelial-mesenchymal transition (EMT), a critical process for malignant transformation of tumor, via the transactivation of β-catenin/lymphoid enhancer-binding factor-1 (LEF-1). These results provide a model to illustrate the relation between FUT8 expression and lung cancer progression and point to a promising direction for the prognosis and therapy of lung cancer.TGF-beta | E-cadherin | fucose F ucosylation, the transfer of fucose from GDP-fucose to glycoconjugates such as glycoproteins and glycolipids, is catalyzed by a family of enzymes called fucosyltransferases (FUTs). So far, 13 FUTs are known to be encoded by the human genome, including FUT1 to 11, protein O-fucosyltransferase 1 (POFUT1), and POFUT2. Through these FUTs, fucoses could be attached to N-, O-, and lipid-linked glycans through an α1,2-(by FUT1 and 2), α1,3-(by FUT3 to 7 and FUT9 to 11), α1,4-(by FUT3 and 5), or α1,6-(by FUT8) linkage, or directly link to the serine/threonine residues of EGF-like or thrombospondin repeats (by POFUT1 and 2, respectively) (1, 2). In mammals, fucosylated glycans have pivotal roles in many aspects of biological processes such as lymphocyte homing, immune responses, fertilization, and development (3). Moreover, aberrant fucosylation, which results from the deficiency or overexpression of FUTs, is associated with a variety of human diseases, including cystic fibrosis, leukocyte adhesion deficiency type II, and cancers (3, 4).Unlike other FUTs, which are functionally redundant, FUT8 is the only enzyme responsible for the α1,6-linked (core) fucosylation by adding fucose to the innermost GlcNAc residue of an N-linked glycan. A growing body of evidence indicates that core fucosylation is important for regulating protein functions. For example, deletion of the core fucose from the Fc region of IgG1 greatly improves its binding affinity to Fcγ receptor IIIa, which in turn enhances antibody-dependent cell-mediated cytotoxicity for over 50 folds (5, 6). Co...

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Ectopic expression of 1,6 fucosyltransferase in mice causes steatosis in the liver and kidney accompanied by a modification of lysosomal acid lipase

Cited by 33 publications

References 48 publications

Analysis ofN-glycan in serum glycoproteins fromdb/dbmice and humans with type 2 diabetes

Analysis ofN-glycan in serum glycoproteins fromdb/dbmice and humans with type 2 diabetes

Physiological roles of N-acetylglucosaminyltransferase V (GnT-V) in mice

Fucosyltransferase 8 as a functional regulator of nonsmall cell lung cancer

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