Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana, United States of America.
PLoS One. 2022 May 9;17(5):e0268260. doi: 10.1371/journal.pone.0268260. eCollection 2022.
Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disorder worldwide and is increasing at an alarming rate. NAFLD is strongly associated with obesity and insulin resistance. The use of animal models remains a vital aspect for investigating the molecular mechanisms contributing to metabolic dysregulation and facilitating novel drug target identification. However, some differences exist between mouse and human hepatocyte physiology. Recently, chimeric mice with human liver have been generated, representing a step forward in the development of animal models relevant to human disease. Here we explored the feasibility of using one of these models (cDNA-uPA/SCID) to recapitulate obesity, insulin resistance and NAFLD upon feeding a Western-style diet. Furthermore, given the importance of a proper control diet, we first evaluated whether there are differences between feeding a purified ingredient control diet that matches the composition of the high-fat diet and feeding a grain-based chow diet. We show that mice fed chow have a higher food intake and fed glucose levels than mice that received a low-fat purified ingredient diet, suggesting that the last one represents a better control diet. Upon feeding a high-fat or matched ingredient control diet for 12 weeks, cDNA-uPA/SCID chimeric mice developed extensive macrovesicular steatosis, a feature previously associated with reduced growth hormone action. However, mice were resistant to diet-induced obesity and remained glucose tolerant. Genetic background is fundamental for the development of obesity and insulin resistance. Our data suggests that using a background that favors the development of these traits, such as C57BL/6, may be necessary to establish a humanized mouse model of NAFLD exhibiting the metabolic dysfunction associated with obesity.
非酒精性脂肪性肝病 (NAFLD) 是全球最常见的慢性肝脏疾病，且发病率呈惊人上升趋势。NAFLD 与肥胖和胰岛素抵抗密切相关。动物模型的应用仍然是研究导致代谢紊乱的分子机制和促进新药物靶点识别的重要方面。然而，老鼠和人类肝细胞的生理学存在一些差异。最近，已经产生了具有人类肝脏的嵌合老鼠，这是开发与人类疾病相关的动物模型的重要一步。在这里，我们探索了使用其中一种模型 (cDNA-uPA/SCID) 在喂食西式饮食时重现肥胖、胰岛素抵抗和非酒精性脂肪性肝病的可行性。此外，鉴于适当对照饮食的重要性，我们首先评估了喂食与高脂肪饮食成分相匹配的纯化成分对照饮食与喂食基于谷物的标准饮食之间是否存在差异。我们发现，喂食标准饮食的老鼠的食物摄入量和葡萄糖水平高于喂食低脂纯化成分饮食的老鼠，这表明后者是更好的对照饮食。在喂食高脂肪或匹配成分对照饮食 12 周后，cDNA-uPA/SCID 嵌合小鼠发展为广泛的大泡性脂肪变性，这一特征以前与生长激素作用降低有关。然而，老鼠对饮食诱导的肥胖具有抵抗力，并且仍然耐受葡萄糖。遗传背景对于肥胖和胰岛素抵抗的发展至关重要。我们的数据表明，使用有利于这些特征发展的背景，例如 C57BL/6，可能对于建立表现出与肥胖相关的代谢功能障碍的人类化 NAFLD 小鼠模型是必要的。
