Circadian Orchestration of the Hepatic Proteome

Abstract

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.

The Mammalian Circadian Timing System: Synchronization of Peripheral Clocks

“…As suggested by genome-wide transcription profiling experiments (Hughes et al 2009 and references therein) and proteomics studies (Reddy et al 2006), the temporal orchestration of metabolism is probably the major purpose of circadian gene expression in the liver and other metabolic organs, such as adipose tissues (Gimble et al 2011) and muscle (Lefta et al 2011). We wish to emphasize that circadian clocks do not work in isolation, but in tight cooperation with acute regulatory mechanisms.…”

Circadian proteomics of the mouse retina

“…Retinal cells are heterogeneous, and cell-type focused analysis including immunohistochemistry is required for understanding physiological roles of oscillating proteins. Recently, Reddy et al [55] reported a circadian proteomic analysis of the mouse liver, in which up to 20% of expressed protein spots showed circadian rhythmicity. The relative abundance of the rhythmic spots derived from the liver proteins may be caused by the effect of nighttime-specific feeding behavior because the liver is the central organ of food metabolism.…”

The role of microRNAs (miRNA) in circadian rhythmicity

“…Yet, analysis of the mammalian cycling proteome revealed that the proportion of cycling cytosolic proteins is rather higher than that found in microarray studies, and that many of the cycling proteins show a constant abundance at the level of the mature transcript (Reddy et al 2006). This discrepancy indicates that posttranscriptional and posttranslational mechanisms (largely unknown) are important components of circadian rhythmicity.…”