Bandsma Robert H J, Smit G Peter A, Kuipers Folkert
Centre for Liver, Digestive and Metabolic Diseases, Room Y2117, CMCIV, University Hospital Groningen, Hanzeplein 1, PO Box 30001, 9700 RB Groningen The Netherlands.
Eur J Pediatr. 2002 Oct;161 Suppl 1:S65-9. doi: 10.1007/s00431-002-1007-8. Epub 2002 Jul 13.
Glycogen storage disease type 1 (GSD1) is an inborn error of metabolism caused by deficiency of glucose-6-phosphatase, the enzyme catalysing the conversion of glucose-6-phosphate (G6P) to glucose. GSD1 is associated with severe hyperlipidaemia and hepatic steatosis. The underlying mechanisms responsible for these abnormalities in lipid metabolism are only partly known. This review summarises data available on hyperlipidaemia and steatosis in GSD1 and postulates new hypotheses for unresolved issues. Evidence indicates that lipid clearance from the blood compartment is decreased in GSD1. Furthermore, in two GSD1a patients synthesis of palmitate, an indicator of de novo lipogenesis, and cholesterol were found to be increased 40-fold and 7-fold, respectively. Elevated hepatic G6P levels may play a regulatory role in lipid synthesis via activation of transcription of lipogenic genes. In addition, accelerated glycolysis will supply acetyl-CoA molecules required for lipogenesis. It is as yet unclear whether hepatic secretion of lipids in the form of very low density lipoprotein-triglycerides (VLDL-TG) is altered in GSD1 patients: we recently found unaffected VLDL-TG secretion rates in an acute animal model of GSD1b. Hepatic steatosis, which is invariably present in GSD1 is probably mainly caused by an increased free fatty acid flux from adipose tissue to the liver and, to a limited extent, by increased de novo lipogenesis.
future studies, using novel stable isotope methodologies, are warranted to further clarify the disturbances in lipid and lipoprotein metabolism in glycogen storage disease type 1 and the role of glucose-6-phosphate herein.
1型糖原贮积病（GSD1）是一种先天性代谢紊乱疾病，由葡萄糖-6-磷酸酶缺乏引起，该酶催化葡萄糖-6-磷酸（G6P）转化为葡萄糖。GSD1与严重的高脂血症和肝脂肪变性有关。脂质代谢异常的潜在机制仅部分为人所知。本综述总结了GSD1中高脂血症和脂肪变性的现有数据，并对未解决的问题提出了新的假设。证据表明，GSD1患者血液中脂质清除率降低。此外，在两名GSD1a患者中，发现从头脂肪生成的指标棕榈酸酯和胆固醇的合成分别增加了40倍和7倍。肝脏G6P水平升高可能通过激活脂肪生成基因的转录在脂质合成中发挥调节作用。此外，加速的糖酵解将提供脂肪生成所需的乙酰辅酶A分子。目前尚不清楚GSD1患者肝脏以极低密度脂蛋白甘油三酯（VLDL-TG）形式分泌脂质是否发生改变：我们最近在GSD1b的急性动物模型中发现VLDL-TG分泌率未受影响。GSD1中始终存在的肝脂肪变性可能主要是由于从脂肪组织到肝脏的游离脂肪酸通量增加，以及在有限程度上由于从头脂肪生成增加所致。
有必要开展进一步研究，采用新型稳定同位素方法，以进一步阐明1型糖原贮积病中脂质和脂蛋白代谢紊乱以及葡萄糖-6-磷酸在此过程中的作用。
