Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada; Centre for Neuromuscular Disease, University of Ottawa, Ottawa, Ontario, Canada.
Department of Biochemistry, Microbiology and Immunology, Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Ontario, Canada.
Cell Mol Gastroenterol Hepatol. 2021;12(1):354-377.e3. doi: 10.1016/j.jcmgh.2021.01.019. Epub 2021 Feb 2.
BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD) is considered a health epidemic with potential devastating effects on the patients and the healthcare systems. Current preclinical models of NAFLD are invariably imperfect and generally take a long time to develop. A mouse model of survival motor neuron (SMN) depletion (Smn mice) was recently shown to develop significant hepatic steatosis in less than 2 weeks from birth. The rapid onset of fatty liver in Smn mice provides an opportunity to identify molecular markers of NAFLD. Here, we investigated whether Smn mice display typical features of NAFLD/nonalcoholic steatohepatitis (NASH).
Biochemical, histologic, electron microscopy, proteomic, and high-resolution respirometry were used.
The Smn mice develop microvesicular steatohepatitis within 2 weeks, a feature prevented by AAV9-SMN gene therapy. Although fibrosis is not overtly apparent in histologic sections of the liver, there is molecular evidence of fibrogenesis and presence of stellate cell activation. The consequent liver damage arises from mitochondrial reactive oxygen species production and results in hepatic dysfunction in protein output, complement, coagulation, iron homeostasis, and insulin-like growth factor-1 metabolism. The NAFLD phenotype is likely due to non-esterified fatty acid overload from peripheral lipolysis subsequent to hyperglucagonemia compounded by reduced muscle use and insulin resistance. Despite the low hepatic mitochondrial content, isolated mitochondria show enhanced β-oxidation, likely as a compensatory response, resulting in the production of reactive oxygen species. In contrast to typical NAFLD/NASH, the Smn mice lose weight because of their associated neurological condition (spinal muscular atrophy) and develop hypoglycemia.
The Smn mice represent a good model of microvesicular steatohepatitis. Like other models, it is not representative of the complete NAFLD/NASH spectrum. Nevertheless, it offers a reliable, low-cost, early-onset model that is not dependent on diet to identify molecular players in NAFLD pathogenesis and can serve as one of the very few models of microvesicular steatohepatitis for both adult and pediatric populations.
非酒精性脂肪性肝病（NAFLD）被认为是一种健康流行病，可能对患者和医疗保健系统造成严重影响。目前，NAFLD 的临床前模型普遍不完善，且通常需要很长时间才能开发出来。最近，存活运动神经元（SMN）耗竭的小鼠模型（Smn 小鼠）从出生后不到 2 周就显示出明显的肝脂肪变性。Smn 小鼠的脂肪肝快速发作为鉴定 NAFLD 的分子标志物提供了机会。在这里，我们研究了 Smn 小鼠是否表现出 NAFLD/非酒精性脂肪性肝炎（NASH）的典型特征。
使用了生化、组织学、电子显微镜、蛋白质组学和高分辨率呼吸测量法。
Smn 小鼠在 2 周内发展为微泡性脂肪性肝炎，AAV9-SMN 基因治疗可预防这一特征。尽管肝组织学切片中没有明显的纤维化，但存在纤维化的分子证据和星状细胞激活的证据。由此产生的肝损伤源于线粒体活性氧的产生，并导致肝脏在蛋白质输出、补体、凝血、铁稳态和胰岛素样生长因子-1 代谢方面的功能障碍。NAFLD 表型可能是由于外周脂肪分解导致的非酯化脂肪酸过载，继而导致高胰高血糖素血症，加上肌肉使用减少和胰岛素抵抗。尽管肝线粒体含量较低，但分离的线粒体显示出增强的β氧化，可能是一种代偿反应，导致活性氧的产生。与典型的 NAFLD/NASH 不同，Smn 小鼠由于其相关的神经状况（脊髓性肌萎缩症）而减轻体重，并出现低血糖。
Smn 小鼠是一种很好的微泡性脂肪性肝炎模型。与其他模型一样，它不能代表完整的 NAFLD/NASH 谱。然而，它提供了一种可靠、低成本、早期发作的模型，不需要依赖饮食来鉴定 NAFLD 发病机制中的分子参与者，并且可以作为成人和儿童微泡性脂肪性肝炎的少数模型之一。
