Ectopic expression of N-acetylglucosaminyltransferase III in transgenic hepatocytes disrupts apolipoprotein B secretion and induces aberrant cellular morphology with lipid storage.
N-Acetylglucosaminyltransferase III (GnT-III) produces "bisecting-GlcNAc" and regulates the branching of N-glycans. GnT-III activity is elevated during hepatocarcinogenesis, which is in contrast to the undetectable level found in normal hepatocytes. To determine the biological significance of GnT-III in hepatocytes, transgenic mice that specifically express GnT-III in the liver were established and characterized. The transgenic hepatocytes had a swollen oval-like morphology, with many lipid droplets. Apolipoprotein B, which contained increased level of bisecting-GlcNAc accumulated in the transgenic hepatocytes. In the transgenic serum, triglycerides, the beta- and pre-beta-lipoprotein fractions, and apolipoprotein B100 were significantly decreased, compared with levels in nontransgenic serum. These abnormal phenotypes were more prominent in the mice with more copies of the transgene and a resulting high GnT-III activity. We demonstrate that aberrant glycosylation, as the direct result of the formation of bisecting-GlcNAc, disrupts the function of apolipoprotein B, leading to the generation of fatty liver. This observation suggests a novel mechanism for the pathogenesis of fatty liver.
Ihara
Y
Y
Department of Biochemistry, Osaka University Medical School, 2-2 Yamadaoka, 1-8 Yamadaoka, Suita, Osaka 565, Japan.
Yoshimura
M
M
Miyoshi
E
E
Nishikawa
A
A
Sultan
A S
AS
Toyosawa
S
S
Ohnishi
A
A
Suzuki
M
M
Yamamura
K
K
Ijuhin
N
N
Taniguchi
N
N
D000818:Animals; D001055:Apolipoproteins B / Q000096:biosynthesis* / Q000097:blood; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D006031:Glycosylation; D008077:Lipoproteins, LDL / Q000097:blood; D008079:Lipoproteins, VLDL / Q000097:blood; D008099:Liver / Q000166:cytology / Q000201:enzymology* / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D017351:N-Acetylglucosaminyltransferases / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D009844:Oligosaccharides / Q000096:biosynthesis / Q000737:chemistry; D011134:Polysaccharides / Q000096:biosynthesis / Q000737:chemistry; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000378:metabolism; D000683:Serum Amyloid P-Component / Q000096:biosynthesis; D014280:Triglycerides / Q000097:blood
D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D009844:Oligosaccharides; D011134:Polysaccharides; D011993:Recombinant Fusion Proteins; D000683:Serum Amyloid P-Component; D014280:Triglycerides; D017351:N-Acetylglucosaminyltransferases; C054599:beta-1,4-mannosyl-glycoprotein beta-1,4-N-acetylglucosaminyltransferase