Rhythmic Nucleotide Synthesis in the Liver: Temporal Segregation of Metabolites

SummaryThe synthesis of nucleotides in the body is centrally controlled by the liver, via salvage or de novo synthesis. We reveal a pervasive circadian influence on hepatic nucleotide metabolism, from rhythmic gene expression of rate-limiting enzymes to oscillating nucleotide metabolome in wild-type (WT) mice. Genetic disruption of the hepatic clock leads to aberrant expression of these enzymes, together with anomalous nucleotide rhythms, such as constant low levels of ATP with an excess in uric acid, the degradation product of purines. These results clearly demonstrate that the hepatic circadian clock orchestrates nucleotide synthesis and degradation. This circadian metabolome timetable, obtained using state-of-the-art capillary electrophoresis time-of-flight mass spectrometry, will guide further investigations in nucleotide metabolism-related disorders.

Graphical AbstractFigure optionsDownload as PowerPoint slideHighlights
► Nucleotide synthesis and degradation is controlled by the hepatic circadian clock
► Disrupting the hepatic clock leads to low nucleotide abundance
► Disrupting the liver clock leads to high urate, suggesting defective purine degradation