Insight review articles
Increased flux through the hexosamine pathway
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| Increased flux through the hexosamine pathway
Shunting of excess intracellular glucose into the hexosamine pathway might also cause several manifestations of diabetic complications 74 . In this pathway, fructose-6-phosphate is diverted from glycolysis to pro- vide substrates for reactions that require UDP-N-acetylglucosamine, such as proteoglycan synthesis and the formation of O-linked glycoproteins (Fig. 4). Inhibition of the rate-limiting enzyme in the conversion of glucose to glucosamine — glutamine:fructose-6-phos- phate amidotransferase (GFAT) — blocks hyperglycaemia-induced increases in the transcription of TGF- a, TGF-b1 (ref. 74) and PAI-1 (ref. 10). This pathway is also important role in hyperglycaemia- induced and fat-induced insulin resistance 75,76 . The mechanism by which increased flux through the hexosamine pathway mediates hyperglycaemia-induced increases in gene insight review articles 816 NATURE | VOL 414 | 13 DECEMBER 2001 | www.nature.com Blood-flow abnormalities Pro-inflammatory gene expression Capillary occlusion Multiple effects Vascular occlusion Vascular permeability Angiogenesis Hyperglycaemia NAD(P)H oxidases Fibrinolysis ROS TGF- β Collagen Fibronectin NF- κ B VEGF PAI-1 eNOS ET-1 DAG PKC ( β - and δ - isoforms) Figure 3 Consequences of hyperglycaemia-induced activation of protein kinase C (PKC). Hyperglycaemia increases diacylglycerol (DAG) content, which activates PKC, primarily the b- and d-isoforms. Activation of PKC has a number of pathogenic consequences by affecting expression of endothelial nitric oxide synthetase (eNOS), endothelin-1 (ET-1), vascular endothelial growth factor (VEGF), transforming growth factor- b (TGF-b) and plasminogen activator inhibitor-1 (PAI-1), and by activating NF- kB and NAD(P)H oxidases. Glucose Glycolytic pathway Glucose Gluc-6-P Fruc-6-P Glucosamine-6-P UDPGlcNAc OGT GFAT Nucleus PA-1 TGF- β 1 Gln Glu AZA – or AS-GFAT PO 4 2– mRNA O-GlcNAc Figure 4 The hexosamine pathway. The glycolytic intermediate fructose-6-phosphate (Fruc-6-P) is converted to glucosamine-6-phosphate by the enzyme glutamine:fructose-6-phosphate amidotransferase (GFAT). Intracellular glycosylation by the addition of N-acetylglucosamine (GlcNAc) to serine and threonine is catalysed by the enzyme O-GlcNAc transferase (OGT). Increased donation of GlcNAc moieties to serine and threonine residues of transcription factors such as Sp1, often at phosphorylation sites, increases the production of factors as PAI-1 and TGF- b1. AZA, azaserine; AS-GFAT, antisense to GFAT. tải về 382.68 Kb. Chia sẻ với bạn bè của bạn:
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