Progressive liver disease and dysregulated glycogen metabolism in murine GSD IX γ2 models human disease

IF 3.7 2区 生物学 Q2 ENDOCRINOLOGY & METABOLISM
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Abstract

Hepatic glycogen storage disease type IX γ2 (GSD IX γ2) is a severe, liver-specific subtype of GSD IX. While all patients with hepatic GSD IX present with similar symptoms, over 95 % of patients with GSD IX γ2 progress to liver fibrosis and cirrhosis. Despite disease severity, the long-term natural history of GSD IX γ2 liver disease progression is not known. Our lab previously characterized the Phkg2−/− mouse model at 3 months of age, demonstrating that the mouse recapitulates the early liver disease phenotype of GSD IX γ2. To understand how liver disease progresses in GSD IX γ2, we characterized the mouse model through 24 months of age. Our study showed for the first time that GSD IX γ2 mice develop liver fibrosis that progresses to cirrhosis. Importantly, we observed that the progression of liver fibrosis is associated with an initial elevation and subsequent decrease of key GSD biomarkers – the latter being a finding that is often considered to be an improvement of disease in patients. In recognition of the unique liver fibrosis pattern and to support future therapeutic investigations using this model, we developed a novel scoring system for GSD IX γ2 mouse liver pathology. Lastly, this work introduces evidence of a dysregulated glycogen metabolism pathway which can serve as an endpoint for future therapeutic evaluation. As we await longitudinal clinical natural history data, these findings greatly expand our understanding of liver disease manifestations in GSD IX γ2 and have notable clinical applications.

Abstract Image

小鼠 GSD IX γ2 人类疾病模型中的渐进性肝病和糖原代谢失调。
肝糖原贮积症 IX γ2型(GSD IX γ2)是 GSD IX 的一种严重的肝脏特异性亚型。虽然所有肝脏 GSD IX 患者的症状相似,但超过 95% 的 GSD IX γ2 患者会发展为肝纤维化和肝硬化。尽管疾病严重,但GSD IX γ2肝病进展的长期自然史尚不清楚。我们的实验室先前鉴定了3月龄的Phkg2-/-小鼠模型,证明该小鼠重现了GSD IX γ2的早期肝病表型。为了了解 GSD IX γ2肝病的发展过程,我们对该小鼠模型进行了长达 24 个月的鉴定。我们的研究首次表明,GSD IX γ2小鼠会出现肝纤维化并发展为肝硬化。重要的是,我们观察到肝纤维化的进展与 GSD 关键生物标志物最初的升高和随后的降低有关,后者通常被认为是患者病情的改善。鉴于这种独特的肝纤维化模式,并为了支持未来利用这种模型进行治疗研究,我们开发了一种新的 GSD IX γ2小鼠肝脏病理学评分系统。最后,这项工作引入了糖原代谢途径失调的证据,可作为未来治疗评估的终点。在我们等待纵向临床自然史数据的同时,这些发现极大地扩展了我们对 GSD IX γ2肝病表现的理解,并具有显著的临床应用价值。
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来源期刊
Molecular genetics and metabolism
Molecular genetics and metabolism 生物-生化与分子生物学
CiteScore
5.90
自引率
7.90%
发文量
621
审稿时长
34 days
期刊介绍: Molecular Genetics and Metabolism contributes to the understanding of the metabolic and molecular basis of disease. This peer reviewed journal publishes articles describing investigations that use the tools of biochemical genetics and molecular genetics for studies of normal and disease states in humans and animal models.
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