Circadian Orchestration of the Hepatic Proteome

Jun 7, 2006Current biology : CB

Daily rhythms control protein levels in the liver

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Abstract

Up to 20% of soluble proteins assayed in mouse liver are subject to circadian control.

Circadian rhythms significantly influence local metabolic processes in the liver.
Many proteins regulated by circadian rhythms are novel and group into distinct phases.
The liver's enzymatic profile varies greatly between day and night due to these rhythmic changes.
Nearly half of the proteins that show circadian variation do not have corresponding changes in their gene expression.
This indicates a substantial role for posttranscriptional mechanisms in regulating circadian rhythms.

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Circadian rhythms are essential to health. Their disruption is associated with metabolic diseases in experimental animals and man. Local metabolic rhythms represent an output of tissue-based circadian clocks. 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. These analyses are inevitably incomplete, not least because metabolic coordination depends ultimately upon temporal regulation of proteins. 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.

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Circadian Orchestration of the Hepatic Proteome

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