Profiling of the circadian metabolome in thioacetamide‐induced liver cirrhosis in mice

Abstract

Liver cirrhosis can disturb circadian rhythms, decreasing patient quality of life. Changes in metabolic products in cirrhosis are poorly understood. We evaluated changes in liver metabolism products using a thioacetamide‐induced mouse model of liver cirrhosis exhibiting circadian rhythm disturbance. Principal component analysis indicated that the circular progression found in the control group was disrupted in the thioacetamide group, and Jonckheere‐Terpstra‐Kendall analysis showed an imbalanced pattern of oscillating metabolic products. In addition to changes in serotonin and other vitamin A–related metabolites, differences in metabolic products associated with energetics, redox homeostasis, bile acid production, inflammation, and other processes were identified. Carbohydrate metabolism showed a reduction in metabolic products associated with the tricarboxylic acid cycle, suggesting up‐regulation of glycolysis and reduced mitochondrial activity. Lipid metabolism showed an increase in ω‐oxidation products, suggesting decreased β‐oxidation. Conclusion: These data will be useful for chronotherapy and modulation of circadian rhythms in patients with liver damage. (Hepatology Communications 2017;1:704–718)

Diurnal regulation of the function of the rat brain glutamate dehydrogenase by acetylation and its dependence on thiamine administration

“…Thus, diurnal regulation of the GDH reactivity to its ligands addresses daily variations in energy metabolism which changes, among others, the levels of the GDH nucleotide regulators (Fustin et al, ; Reinke & Asher, ). Remarkably, the levels of 2‐oxoglutarate are not altered between the corresponding time points (Fujisawa, Takami, Matsumoto, Yamamoto, & Sakaida, ). Stabilization of GDH function (Figure a and b) through the adjustments of the GDH affinities to the oscillating nucleotide regulators (Table ) may contribute to this constant level of 2‐oxoglutarate.…”

Adropin as a potential mediator of the metabolic system‐autonomic nervous system‐chronobiology axis: Implementing a personalized signature‐based platform for chronotherapy

“…Liver metabolic pathways and liver nuclear receptors are regulated by circadian clocks, reflected by oscillatory hormone binding, energy flux and expenditure and connected with metabolite production 77 . Studies have shown that disruption of the clock system plays a significant role in the development of alcoholic liver disease (ALD), liver fibrosis, liver cirrhosis, nonalcoholic fatty liver disease and hepatic carcinoma 78–81 …”

“…77 Studies have shown that disruption of the clock system plays a significant role in the development of alcoholic liver disease (ALD), liver fibrosis, liver cirrhosis, nonalcoholic fatty liver disease and hepatic carcinoma. [78][79][80][81] Disruption of intestinal barrier function contributes to the devel- intestinal hyperpermeability. 82 The clock gene mPer2 controls circadian periods and its deficiency is associated with acute liver injury in mice by predisposing them to liver fibrosis by increasing HSC activation and inhibiting HSC apoptosis.…”

Immunometabolism: A novel perspective of liver cancer microenvironment and its influence on tumor progression

“…These strong oxidizing products promote inflammation, fibrosis, and even carcinogenesis. Lipid metabolism shows an alteration from β-oxidation to ω-oxidation during liver cirrhosis[ 104 ]. Intriguingly, a metabolic switch from oxidative phosphorylation to glycolysis in hepatocytes in early-stage cirrhosis may satisfy the extreme energy requirements under such conditions[ 105 ].…”