BACKGROUND After proteolysis, the majority of released amino acids from dietary protein are transported to the liver for gluconeogenesis or to peripheral tissues where they are used for protein synthesis and eventually catabolized, producing ammonia as a byproduct. High ammonia levels in the brain are a major contributor to the decreased neural function that occurs in several pathological conditions such as hepatic encephalopathy when liver urea cycle function is compromised. Therefore, it is important to gain a deeper understanding of human ammonia metabolism. The objective of this study was to predict changes in blood ammonia levels resulting from alterations in dietary protein intake, from liver disease, or from partial loss of urea cycle function. METHODS A simple mathematical model was created using MATLAB SimBiology and data from published studies. Simulations were performed and results analyzed to determine steady state changes in ammonia levels resulting from varying dietary protein intake and varying liver enzyme activity levels to simulate liver disease. As a toxicity reference, viability was measured in SH-SY5Y neuroblastoma cells following differentiation and ammonium chloride treatment. RESULTS Results from control simulations yielded steady state blood ammonia levels within normal physiological limits. Increasing dietary protein intake by 72% resulted in a 59% increase in blood ammonia levels. Simulations of liver cirrhosis increased blood ammonia levels by 41 to 130% depending upon the level of dietary protein intake. Simulations of heterozygous individuals carrying a loss of function allele of the urea cycle carbamoyl phosphate synthetase I (CPS1) gene resulted in more than a tripling of blood ammonia levels (from roughly 18 to 60 μM depending on dietary protein intake). The viability of differentiated SH-SY5Y cells was decreased by 14% by the addition of a slightly higher amount of ammonium chloride (90 μM). CONCLUSIONS Data from the model suggest decreasing protein consumption may be one simple strategy to decrease blood ammonia levels and minimize the risk of developing hepatic encephalopathy for many liver disease patients. In addition, the model suggests subjects who are known carriers of disease-causing CPS1 alleles may benefit from monitoring blood ammonia levels and limiting the level of protein intake if ammonia levels are high.

中文翻译：

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高蛋白饮食和肝脏疾病对人体氨代谢的计算机模型的影响。


背景技术蛋白水解后，膳食蛋白质中释放的大部分氨基酸被转运至肝脏进行糖异生或转运至外周组织，在那里它们用于蛋白质合成并最终分解代谢，产生副产物氨。大脑中的高氨水平是导致神经功能下降的主要原因，这种下降在多种病理状况下发生，例如当肝脏尿素循环功能受损时发生肝性脑病。因此，深入了解人体氨代谢非常重要。本研究的目的是预测由于膳食蛋白质摄入量改变、肝脏疾病或尿素循环功能部分丧失而导致的血氨水平变化。方法 使用 MATLAB SimBiology 和已发表研究的数据创建了一个简单的数学模型。进行模拟并分析结果，以确定由于不同的膳食蛋白质摄入量和不同的肝酶活性水平而导致的氨水平的稳态变化，以模拟肝脏疾病。作为毒性参考，在分化和氯化铵处理后测量 SH-SY5Y 神经母细胞瘤细胞的活力。结果 控制模拟的结果产生了正常生理限度内的稳态血氨水平。膳食蛋白质摄入量增加 72% 导致血氨水平增加 59%。肝硬化的模拟使血氨水平增加 41% 至 130%，具体取决于膳食蛋白质摄入量的水平。 对携带尿素循环氨基甲酰磷酸合成酶 I (CPS1) 基因功能缺失等位基因的杂合个体进行模拟，导致血氨水平增加三倍以上（从大约 18 到 60 μM，具体取决于膳食蛋白质摄入量）。添加稍高量的氯化铵 (90 μM) 后，分化的 SH-SY5Y 细胞的活力降低了 14%。结论 该模型的数据表明，减少蛋白质消耗可能是降低血氨水平并最大程度降低许多肝病患者发生肝性脑病风险的一种简单策略。此外，该模型表明已知致病 CPS1 等位基因携带者的受试者可能会受益于监测血氨水平并在氨水平较高时限制蛋白质摄入水平。