Section on Cellular Differentiation, Program on Developmental Endocrinology and Genetics, National Institute of Child Health and Human Development, Bethesda, MD 20892-1830, USA.
J Hepatol. 2009 Nov;51(5):909-17. doi: 10.1016/j.jhep.2008.11.026. Epub 2009 Feb 5.
BACKGROUND/AIMS: Glycogen storage disease type Ib (GSD-Ib) patients deficient in a glucose-6-phosphate transporter (G6PT) manifest disturbed glucose homeostasis, myeloid dysfunctions, and hepatocellular adenoma (HCA). This study was conducted to evaluate whether maintaining normoglycemia in GSD-Ib could prevent HCA.
We infused neonatal GSD-Ib mice with adeno-associated virus (AAV) carrying G6PT and examined their metabolic and myeloid phenotypes for the 72-week study.
The AAV vector delivered the G6PT transgene to the liver and bone marrow. Long-term metabolic correction was achieved alongside a transient myeloid correction. Hepatic G6PT activity was 50% of wild-type levels at 2 weeks post-infusion but declined rapidly thereafter to reach 3% of wild-type levels by age 6 to 72 weeks. Despite this, the infused mice maintained normoglycemia throughout the study, exhibited near normal growth and normalized serum metabolite profiles. However, all five AAV-treated GSD-Ib mice that lived over 50 weeks accumulated excessive hepatic glycogen and fat. Two mice developed steatohepatitis and multiple HCAs with one undergoing malignant transformation.
Normoglycemia alone cannot prevent hepatic steatosis and glycogen accumulation or the development of HCAs in GSD-Ib, providing one explanation why GSD-Ib patients maintaining normoglycemia under intense dietary therapy continue at risk for this long-term complication.
背景/目的:缺乏葡萄糖-6-磷酸转运蛋白(G6PT)的糖原贮积病 Ib 型(GSD-Ib)患者表现出葡萄糖稳态紊乱、髓系功能障碍和肝细胞腺瘤(HCA)。本研究旨在评估在 GSD-Ib 中维持正常血糖是否可以预防 HCA。
我们用携带 G6PT 的腺相关病毒(AAV)对新生 GSD-Ib 小鼠进行输注,并在 72 周的研究中检查其代谢和髓系表型。
AAV 载体将 G6PT 转基因递送到肝脏和骨髓。实现了长期代谢矫正,并伴有短暂的髓系矫正。肝 G6PT 活性在输注后 2 周达到野生型水平的 50%,但此后迅速下降,到 6 至 72 周时达到野生型水平的 3%。尽管如此,输注小鼠在整个研究过程中保持正常血糖,表现出接近正常的生长和正常的血清代谢物谱。然而,所有五只存活超过 50 周的 AAV 治疗的 GSD-Ib 小鼠都积累了过多的肝糖原和脂肪。两只小鼠发生了脂肪性肝炎和多个 HCA,其中一只发生了恶性转化。
仅维持正常血糖不能预防 GSD-Ib 中的肝脂肪变性和糖原积累或 HCA 的发展,这解释了为什么在强化饮食治疗下维持正常血糖的 GSD-Ib 患者仍面临这种长期并发症的风险。