N-Acetylglucosaminyltransferase V regulates TGF-β response in hepatic stellate cells and the progression of steatohepatitis.

Abstract

N-Acetylglucosaminyltransferase V (GnT-V), catalyzing β1-6 branching in asparagine-linked oligosaccharides, is one of the most important glycosyltransferases involved in tumor metastasis and carcinogenesis. Although the expression of GnT-V is induced in chronic liver diseases, the biological meaning of GnT-V in the diseases remains unknown. The aim of this study was to investigate the effects of GnT-V on the progression of chronic hepatitis, using GnT-V transgenic (Tg) mice fed a high fat and high cholesterol (HFHC) diet, an experimental model of murine steatohepatitis. Although enhanced hepatic lymphocytes infiltration and fibrosis were observed in wild-type (WT) mice fed the HFHC diet, they were dramatically prevented in Tg mice. In addition, the gene expression of inflammatory Th1 cytokines in the liver was significantly decreased in Tg mice than WT mice. Inhibition of liver fibrosis was due to the dysfunction of hepatic stellate cells (HSCs), which play pivotal roles in liver fibrosis through the production of transforming growth factor (TGF)-β1. Although TGF-β1 signaling was enhanced in Tg mouse-derived HSCs (Tg-HSCs) compared with WT mouse-derived HSCs (WT-HSCs), collagen expression was significantly reduced in Tg-HSCs. As a result from DNA microarray, cyclooxygenase-2 (COX2) expression, known as a negative feedback signal for TGF-β1, was significantly elevated in Tg-HSCs compared with WT-HSCs. Prostaglandin E2 (PGE2), the product of COX2, production was also significantly elevated in Tg-HSCs. COX2 inhibition by celecoxib decreased PGE2 and increased collagen expression in Tg-HSCs. In conclusion, GnT-V prevented steatohepatitis progression through modulating lymphocyte and HSC functions.

• Authors: Yoshihiro Kamada, Kanako Mori, Hitoshi Matsumoto, Shinichi Kiso, Yuichi Yoshida, Shinichiro Shinzaki, Naoki Hiramatsu, Mayuko Ishii, Kenta Moriwaki, Norifumi Kawada, Tetsuo Takehara, Eiji Miyoshi
• Journal: Glycobiology (Glycobiology) Vol. 22 Issue 6 Pg. 778-87 (Jun 2012) ISSN: 1460-2423 [Electronic] England
• PMID: 22294551 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Pyrazoles
• Sulfonamides
• Transforming Growth Factor beta
• Cyclooxygenase 2
• N-Acetylgalactosaminyltransferases
• Celecoxib

Topics

• Animals
• Celecoxib
• Cyclooxygenase 2 (biosynthesis, metabolism)
• Fatty Liver (enzymology, metabolism)
• Hepatic Stellate Cells (enzymology, metabolism)
• Male
• Mice
• Mice, Transgenic
• N-Acetylgalactosaminyltransferases (metabolism)
• Pyrazoles (pharmacology)
• Sulfonamides (pharmacology)
• Transforming Growth Factor beta (metabolism)