Circadian orchestration of the hepatic Proteome

Circadian rhythms are essential to health. Their disruption is associated with metabolic diseases in experimental animals and man [1-3]. Local metabolic rhythms represent an output of tissue-based circadian clocks [4]. Attempts to define how local metabolism is temporally coordinated have focused on gene expression by defining extensive and divergent "circadian transcriptomes" involving 5%-10% of genes assayed [5-8]. These analyses are inevitably incomplete, not least because metabolic coordination depends ultimately upon temporal regulation of proteins [9, 10]. We therefore conducted a systematic analysis of a mammalian "circadian proteome." Our analysis revealed that up to 20% of soluble proteins assayed in mouse liver are subject to circadian control. Many of these circadian proteins are novel and cluster into discrete phase groups so that the liver's enzymatic profile contrasts dramatically between day and night. Unexpectedly, almost half of the cycling proteins lack a corresponding cycling transcript, as determined by quantitative PCR, microarray, or both and revealing for the first time the extent of posttranscriptional mechanisms as circadian control points. The circadian proteome includes rate-limiting factors in vital pathways, including urea formation and sugar metabolism. These findings provide a new perspective on the extensive contribution of circadian programming to hepatic physiology.