RESUMO
The intricate connection between the circadian clock and metabolism remains poorly understood. We used high temporal resolution metabolite profiling to explore clock regulation of mouse liver and cell-autonomous metabolism. In liver, â¼50% of metabolites were circadian, with enrichment of nucleotide, amino acid, and methylation pathways. In U2 OS cells, 28% were circadian, including amino acids and NAD biosynthesis metabolites. Eighteen metabolites oscillated in both systems and a subset of these in primary hepatocytes. These 18 metabolites were enriched in methylation and amino acid pathways. To assess clock dependence of these rhythms, we used genetic perturbation. BMAL1 knockdown diminished metabolite rhythms, while CRY1 or CRY2 perturbation generally shortened or lengthened rhythms, respectively. Surprisingly, CRY1 knockdown induced 8 hr rhythms in amino acid, methylation, and vitamin metabolites, decoupling metabolite from transcriptional rhythms, with potential impact on nutrient sensing in vivo. These results provide the first comprehensive views of circadian liver and cell-autonomous metabolism.
Assuntos
Relógios Circadianos/genética , Metaboloma/genética , Transcrição Gênica , Animais , Linhagem Celular Tumoral , Células Cultivadas , Ritmo Circadiano/genética , Creatina/metabolismo , Criptocromos/metabolismo , Redes Reguladoras de Genes , Hepatócitos/metabolismo , Humanos , Fígado/metabolismo , Camundongos , Nitrogênio/metabolismo , Fatores de TempoRESUMO
Light is a very important environmental factor that governs many cellular responses in organisms. As a consequence, organisms possess different kinds of light-sensing photoreceptors to regulate their physiological variables and adapt to a given habitat. The cryptochrome/photolyase family (CPF) includes photoreceptors that perform different functions in different organisms. Photolyases repair ultraviolet-induced DNA damage by a process known as photoreactivation using photons absorbed from the blue end of the light spectrum. On the other hand, cryptochromes act as blue light circadian photoreceptors in plants and Drosophila to regulate growth and development. In mammals, cryptochromes have light-independent functions and are very important transcriptional regulators that act at the molecular level as negative transcriptional regulators of the circadian clock. In this review, we highlight current knowledge concerning the structural and functional relationships of CPF members.
