Effects of a high protein diet and liver disease in an in silico model of human ammonia metabolism

Abstract

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. Electronic supplementary material The online version of this article (10.1186/s12976-019-0109-1) contains supplementary material, which is available to authorized users.

Liver injury in non-alcoholic fatty liver disease is associated with urea cycle enzyme dysregulation

“…In a recent study where authors created a mathematical model to determine changes in ammonia levels from variable dietary protein intake and varying liver enzyme activity, it was reported that CPS1 activity had by far the strongest effect on blood ammonia levels of any other enzyme of the model. They demonstrated that 50% of decreased CPS1 activity led to a more of doubling in blood ammonia levels, as well as the decrease of protein intake may decrease blood ammonia levels minimizing the risk of developing hepatic encephalopathy 16 . Further, it was recently demonstrated that using a metabolite panel reflecting defects in ammonia recycling, urea cycle and amino acid metabolism could detect patients at risk of hepatocellular carcinoma 17 .…”

Essential Amino Acid Supplement Lowers Intrahepatic Lipid despite Excess Alcohol Consumption

“…In these circumstances, a nutritional supplement designed to address the specific metabolic issues associated with the condition may provide unique benefits. A variety of nutritional supplements targeting some aspect of the AUD responses are available or have been proposed [8][9][10][11][12][13][14][15][16][17][18][19][20]. However, none have corrected the disruptions in macronutrient metabolism that lead to hepatic steatosis [11].…”

“…The etiology of hepatic steatosis is not identical among those at risk for metabolic disease and those who present with AUD [17]. Hepatic steatosis can occur in part because of a limitation in mitochondrial function [18], and thus impaired fatty acid oxidative capacity [19]. Impaired fatty acid oxidation results in the channeling of fatty acids into triglyceride synthesis.…”

Two Siblings With Valproate-Related Hyperammonemia and Novel Mutations in Glutamine Synthetase (GLUL) Treated With Carglumic Acid

“…1,2 Hyperammonemia typically occurs when plasma ammonia levels are above 50 umol/L; the exposure of the central nervous system to such an environment can lead to encephalopathy at levels double that. 3 Changes in neuronal pH, neuronal membrane potentials, astrocytic swelling, altered neurotransmitter response, and changes in cerebral energy metabolism and reduced ATP are considered some of the mechanisms of ammonia neurotoxicity. 4,5 Hyperammonemic disorders can be due to liver dysfunction, side-effects from certain medications (valproic acid, topiramate, carbamazepine, thiazides, isoniazid, or chemotherapies), impaired circulation where portal vein flow to the liver is reduced (because of obstruction or surgical bypass), or inborn errors of metabolism.…”