Institute of Biochemistry, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Charitéplatz 1, 10117 Berlin, Germany.
Institute for Imaging Science and Computational Modelling in Cardiovascular Medicine, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
Cells. 2021 Mar 5;10(3):578. doi: 10.3390/cells10030578.
Non-Alcoholic Fatty Liver Disease (NAFLD) is the most common type of chronic liver disease in developed nations, affecting around 25% of the population. Elucidating the factors causing NAFLD in individual patients to progress in different rates and to different degrees of severity, is a matter of active medical research. Here, we aim to provide evidence that the intra-hepatic heterogeneity of rheological, metabolic and tissue-regenerating capacities plays a central role in disease progression. We developed a generic mathematical model that constitutes the liver as ensemble of small liver units differing in their capacities to metabolize potentially cytotoxic free fatty acids (FFAs) and to repair FFA-induced cell damage. Transition from simple steatosis to more severe forms of NAFLD is described as self-amplifying process of cascading liver failure, which, to stop, depends essentially on the distribution of functional capacities across the liver. Model simulations provided the following insights: (1) A persistently high plasma level of FFAs is sufficient to drive the liver through different stages of NAFLD; (2) Presence of NAFLD amplifies the deleterious impact of additional tissue-damaging hits; and (3) Coexistence of non-steatotic and highly steatotic regions is indicative for the later occurrence of severe NAFLD stages.
非酒精性脂肪性肝病（NAFLD）是发达国家最常见的慢性肝病，影响大约 25%的人口。阐明导致个体患者 NAFLD 以不同速度和不同严重程度进展的因素，是医学研究的一个活跃领域。在这里，我们旨在提供证据表明，肝脏内的流变学、代谢和组织再生能力的异质性在疾病进展中起着核心作用。我们开发了一个通用的数学模型，将肝脏视为具有不同代谢潜在细胞毒性游离脂肪酸（FFAs）和修复 FFA 诱导的细胞损伤能力的小肝单位的集合。从单纯性脂肪变性到更严重的 NAFLD 形式的转变被描述为肝衰竭的级联自我放大过程，要停止该过程，主要取决于肝脏内功能能力的分布。模型模拟提供了以下见解：（1）持续高水平的血浆 FFA 足以使肝脏经历不同阶段的 NAFLD；（2）NAFLD 的存在放大了其他组织损伤的有害影响；（3）非脂肪变性和高度脂肪变性区域共存提示随后发生严重的 NAFLD 阶段。
