• biological sciences
• human metabolism
• mathematical biosciences

Dietary threonine (Thr) deficiency increases hepatic triglyceride accumulation in Pekin ducks, which results in fatty liver disease and impairs hepatic function. However, the underlying molecular mechanisms altered by dietary Thr deficiency are still unknown. To identify the underlying molecular changes, 180 one-day-old ducklings were divided into three groups, including Thr deficiency group (Thr-D), Thr sufficiency group (Thr-S), and pair-fed group (Pair-F) that was fed with a Thr-sufficient diet but with reduced daily feed intake. The results showed that feed intake was similar between Thr-D and Pair-F groups, but weight gain rate and final body weight in the Thr-D group were lower than those in the Pair-F group. Feed intake, weight gain, and body weight in Thr-D and Pair-F groups were lower than those in the Thr-S group. The Thr-D diet reduced abdominal fat percentage but increased hepatic triglyceride content when compared with that of the Thr-S and Pair-F groups. The Pair-F reduced hepatic levels of C15:0, C17:0, C18:0, C20:0, C20:4n6, and C22:0 and also reduced total fatty acid, saturated fatty acid, and unsaturated fatty acid content when compared with those of the Thr-D and Thr-S groups. The Thr-D diet increased hepatic content of C6:0, C17:1, C18:3n6, C20:0, C20:1n9, and C22:2, as well as reduced the content of C18:2n6t and C23:0 when compared with those of the Thr-S group. Transcriptome analysis in the liver indicated that the Thr-D diet upregulated genes related to fatty acid and triglyceride synthesis and downregulated genes related to fatty acid oxidation and triglyceride transport. Gene ontology analysis showed that more genes related to lipid metabolism processes and molecular function were differentially expressed in the Thr-D group relative to Thr-S and Pair-F groups than in the Pair-F group relative to the Thr-S group. KEGG pathway analysis showed that differentially expressed genes were enriched in signal transduction, immune, hormone, lipid, and amino acid metabolism pathways. Our findings indicated that the Thr-D diet increased hepatic triglyceride and fatty acid accumulation via increasing fatty acid and triglyceride synthesis and reducing fatty acid oxidation and triglyceride transport. These findings provide novel insights into our understanding of the molecular mechanisms underlying fat accumulation in the liver caused by dietary threonine deficiency.

• Pekin duck
• energy metabolism
• fatty acid oxidation
• fatty acid profile
• threonine deficiency
• triglyceride accumulation

• Amino acids
• Branched chain amino acids
• Cirrhosis
• Diet
• Fischer’s ratio
• Liver
• Nutrition
• Protein
• Tolerance

Adrenal toxicity is one of the major concerns in drug development. To quantitatively understand the effect of endocrine-active compounds on adrenal steroidogenesis and to assess the human adrenal toxicity of novel pharmaceutical drugs, we developed a mathematical model of steroidogenesis in human adrenocortical carcinoma NCI-H295R cells. The model includes cellular proliferation, intracellular cholesterol translocation, diffusional transport of steroids, and metabolic pathways of adrenal steroidogenesis, which serially involve steroidogenic proteins and enzymes such as StAR, CYP11A1, CYP17A1, HSD3B2, CYP21A2, CYP11B1, CYP11B2, HSD17B3, and CYP19A1. It was reconstructed in an experimental dynamics of cholesterol and 14 steroids from an in vitro steroidogenesis assay using NCI-H295R cells. Results of dynamic sensitivity analysis suggested that HSD3B2 plays the most important role in the metabolic balance of adrenal steroidogenesis. Based on differential metabolic profiling of 12 steroid hormones and 11 adrenal toxic compounds, we could estimate which steroidogenic enzymes were affected in this mathematical model. In terms of adrenal steroidogenic inhibitors, the predicted action sites were approximately matched to reported target enzymes. Thus, our computer-aided system based on systems biological approach may be useful to understand the mechanism of action of endocrine-active compounds and to assess the human adrenal toxicity of novel pharmaceutical drugs.

One of the most important projects in the post-genome-era is the systemic identification of biological network. The almost of studies for network identification focused on the improvement of computational efficiency in large-scale network inference of complex system with cyclic relations and few attempted have been done for answering practical problem occurred in real biological systems. In this study, we focused to evaluate inferring performance of our previously proposed method for inferring biological network on simple network motifs.

We evaluated the network inferring accuracy and efficiency of our previously proposed network inferring algorithm, by using 6 kinds of repeated appearance of highly significant network motifs in the regulatory network of E. coli proposed by Shen-Orr et al and Herrgård et al, and 2 kinds of network motif in S. cerevisiae proposed by Lee et. al. As a result, our method could reconstruct about 40% of interactions in network motif from time-series data set. Moreover the introduction of time-series data of one-factor disrupted model could remarkably improved the performance of network inference.

The results of network inference examination of E. coli network motif shows that our network inferring algorithm was able to apply to typical topology of biological network. A continuous examination of inferring well established network motif in biology would strengthen the applicability of our algorithm to the realistic biological network.

Amino acids are a group of metabolites that are important substrates for protein synthesis, are important as signaling molecules and play central roles as highly connected metabolic hubs, and therefore, there are many reports that describe disease-specific abnormalities in plasma amino acids profile. However, the causes of progression from a healthy control to a manifestation of the plasma amino acid changes remain obscure. Here, we extended the plasma amino acids profile to relationships that have interactive properties, and found remarkable differences in the longitudinal transition of hyperglycemia as a diabetes emergency. What is especially important is to understand pathogenesis for better treatment and early diagnosis of diabetes. In this study, we performed interactive analysis using time course data of the plasma samples of AKITA mice, which develop hyperglycemia. Primarily, we decided to analyze the interactive property of amino acids which had highly significant association with hyperglycemia, namely alanine, glycine, leucine, isoleucine and valine. Next, we inferred the interactive network structure, which reproduces the actual time course within an error allowance of 10% using an S-system model (a conceptual mathematical model for analyzing and simulating networks). The emphasis of this study was altered interactions of plasma amino acids that show stabilizing and destabilizing features in a variety of clinical settings. By performing sensitivity analysis, the most dominant relations in this network were selected; the control paths from glycine to isoleucine in healthy control and from alanine to glycine in hyperglycemia. This result is in good agreement with the biological knowledge regarding branched-chain amino acids, and suggests the biological importance of the effect from alanine to glycine.

• Hyperglycemia
• Interactive network analysis
• Plasma amino acids
• Time course data

• Amino Acids, Essential/blood
• Amino Acids, Essential/deficiency
• Animals
• Body Weight/physiology
• Diet
• Estrous Cycle/physiology
• Feeding Behavior/physiology
• Female
• Hormones/blood
• Liver/metabolism
• Organ Size/physiology
• Ovary/metabolism
• Rats

From an evolutionary perspective, the ancestors of cetaceans first lived in terrestrial environments prior to adapting to aquatic environments. Whereas anatomical and morphological adaptations to aquatic environments have been well studied, few studies have focused on physiological changes. We focused on plasma amino acid concentrations (aminograms) since they show distinct patterns under various physiological conditions. Plasma and urine aminograms were obtained from bottlenose dolphins, pacific white-sided dolphins, Risso's dolphins, false-killer whales and C57BL/6J and ICR mice. Hierarchical cluster analyses were employed to uncover a multitude of amino acid relationships among different species, which can help us understand the complex interrelations comprising metabolic adaptations. The cetacean aminograms formed a cluster that was markedly distinguishable from the mouse cluster, indicating that cetaceans and terrestrial mammals have quite different metabolic machinery for amino acids. Levels of carnosine and 3-methylhistidine, both of which are antioxidants, were substantially higher in cetaceans. Urea was markedly elevated in cetaceans, whereas the level of urea cycle-related amino acids was lower. Because diving mammals must cope with high rates of reactive oxygen species generation due to alterations in apnea/reoxygenation and ischemia-reperfusion processes, high concentrations of antioxidative amino acids are advantageous. Moreover, shifting the set point of urea cycle may be an adaption used for body water conservation in the hyperosmotic sea water environment, because urea functions as a major blood osmolyte. Furthermore, since dolphins are kept in many aquariums for observation, the evaluation of these aminograms may provide useful diagnostic indices for the assessment of cetacean health in artificial environments in the future.

• Amino Acids/blood
• Amino Acids/metabolism
• Amino Acids/urine
• Analysis of Variance
• Animals
• Carnosine/blood
• Cluster Analysis
• Creatinine/urine
• Dolphins
• Female
• Male
• Methylhistidines/blood
• Mice
• Mice, Inbred C57BL
• Mice, Inbred ICR
• Species Specificity
• Urea/metabolism
• Whales

• Amino Acids/metabolism
• Animals
• Argininosuccinate Lyase/genetics
• Argininosuccinate Lyase/metabolism
• Insulin/blood
• Liver/enzymology
• Liver/metabolism
• Lysine/deficiency
• Lysine/metabolism
• Male
• Motor Activity/physiology
• Muscle Proteins/biosynthesis
• Muscle Proteins/metabolism
• Muscle, Skeletal/metabolism
• Phosphoglycerate Dehydrogenase/genetics
• Phosphoglycerate Dehydrogenase/metabolism
• RNA/chemistry
• RNA/genetics
• Random Allocation
• Rats
• Rats, Wistar
• Reverse Transcriptase Polymerase Chain Reaction
• Urea/blood