The Liver in the Eyes of a Chronobiologist

Our understanding of the molecular underpinnings of the mammalian circadian oscillator and its tight connection to physiology has progressed tremendously during the past decades. The liver is considered the prototypic experimental model tissue for circadian research in peripheral organs. Studies on liver clocks have been highly productive and yielded information about widely different aspects of circadian biology. The liver, as one of the largest organs in the body, has often been used for the identification of core clock and auxiliary clock components, for example, by biochemical purifications. Because the liver is also a major metabolic hub, studies addressing the interplay between circadian clocks and metabolism have been insightful. In addition, the use of liver-specific loss-of-function models for clock components highlighted not only specific physiological roles of the hepatic clock but also its interplay with systemic cues and oscillators in other organs. Recently, technological advances in omics approaches have been successfully applied on the liver, providing a comprehensive depiction of pervasive circadian control of gene expression and protein and metabolite accumulation. In this review, we chose to illuminate specific examples that demonstrate how different experimental approaches--namely, biochemical, metabolic, genetic, and omics methodologies--have advanced our knowledge regarding circadian liver biology and chronobiology in general.