Circadian Rhythms of Liver Enzymes and Their Relationship to Enzyme Induction

Civen, Morton; Ulrich, R.W.; Trimmer, Betty M.; Brown, Charlesta B.

doi:10.1126/science.157.3796.1563

Cited by 97 publications

(17 citation statements)

References 11 publications

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“…Additional rhythmicity in gene expression is generated by rhythmic posttranscriptional regulation (3). Circadian rhythms have been detected in mRNA and protein abundances (4)(5)(6), enzyme activities (7,8), and concentrations of metabolites (9)(10)(11) in various mammalian tissues. Whereas the mechanisms underlying rhythmic gene expression are relatively well-studied, it remains unclear how circadian gene expression induces rhythms in the abundance of metabolites or metabolic fluxes.…”

mentioning

confidence: 99%

Principles for circadian orchestration of metabolic pathways

Thurley

Herbst

Wesener

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Circadian rhythms govern multiple aspects of animal metabolism. Transcriptome-, proteome-and metabolome-wide measurements have revealed widespread circadian rhythms in metabolism governed by a cellular genetic oscillator, the circadian core clock. However, it remains unclear if and under which conditions transcriptional rhythms cause rhythms in particular metabolites and metabolic fluxes. Here, we analyzed the circadian orchestration of metabolic pathways by direct measurement of enzyme activities, analysis of transcriptome data, and developing a theoretical method called circadian response analysis. Contrary to a common assumption, we found that pronounced rhythms in metabolic pathways are often favored by separation rather than alignment in the times of peak activity of key enzymes. This property holds true for a set of metabolic pathway motifs (e.g., linear chains and branching points) and also under the conditions of fast kinetics typical for metabolic reactions. By circadian response analysis of pathway motifs, we determined exact timing separation constraints on rhythmic enzyme activities that allow for substantial rhythms in pathway flux and metabolite concentrations. Direct measurements of circadian enzyme activities in mouse skeletal muscle confirmed that such timing separation occurs in vivo.circadian rhythms | glucose metabolism | metabolic response analysis | mouse skeletal muscle C ircadian rhythms are ∼24-h cycles in behavior, physiology, and cellular processes that persist in the absence of external cues. In mammals, circadian rhythms in the expression of thousands of genes in various metabolic tissues ensure up-or down-regulation of important metabolic processes in anticipation of daily activity and rest periods (1, 2). Circadian gene expression in mammalian tissues depends on the circadian core clock, a genetic feedback oscillator inducing the transcription of thousands of clock-controlled genes. Additional rhythmicity in gene expression is generated by rhythmic posttranscriptional regulation (3). Circadian rhythms have been detected in mRNA and protein abundances (4-6), enzyme activities (7, 8), and concentrations of metabolites (9-11) in various mammalian tissues. Whereas the mechanisms underlying rhythmic gene expression are relatively well-studied, it remains unclear how circadian gene expression induces rhythms in the abundance of metabolites or metabolic fluxes.A naïve picture of circadian regulation (Fig. 1A) ("central dogma of molecular chronobiology") suggests that the circadian core clock drives rhythmic mRNA expression, resulting in rhythmic protein levels and directly leading to rhythmic enzyme activity (12) and thus, metabolic activity. Here, especially metabolic pathway flux (rate of conversion of substrate into product metabolites measured in concentration per time; an analogy is water flow through a floodgate) has been regarded as a crucial biological function under strong evolutionary selection pressure (13,14). However, it is unclear whether circadian abundances of enzyme trans...

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mentioning

confidence: 99%

Principles for circadian orchestration of metabolic pathways

Thurley

Herbst

Wesener

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…2.6.1.5) in the rat liver varies over a two-to fourfold range daily (Potter et al 1966). From low daytime values enzyme activity increases to peak several hours after darkness (Civen, Ulrich, Trimmer & Brown, 1967;Shambaugh, Warner & Beisel, 1967;Wurtman & Axelrod, 1967). This rise to an evening peak represents in-ACh, VAGUS AND TYROSINE TRANSAMINASE 423 by the inability of randomly selected animals to survive 1 week on tap water and confirmed after death in all animals by inspection of the retroperitoneal space for any remaining adrenal tissue.…”

Section: Introductionmentioning

confidence: 99%

Cholinergic regulation of hepatic tyrosine transaminase activity

Black¹,

Reis²

1971

The Journal of Physiology

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SUMMARY1. The cholinergic agent carbachol (0.5 mg/kg) produces within 2 hr a two-to threefold increase in the activity of hepatic tyrosine transaminase in the adrenalectomized fasted rat.2. The carbachol-evoked rise in enzyme activity is prevented by pretreatment with atropine.3. Cycloheximide, an inhibitor of protein synthesis, prevents the carbachol-evoked rise of enzyme activity; actinomycin D, an inhibitor of RNA synthesis, partially reduces it. 4. Atropine or unilateral (right or left) vagotomy suppresses the daily rhythm of tyrosine transaminase by attenuating the normal evening peak but not the normal lower daily levels of the enzyme.5. Electrical stimulation of the right vagus results in a significant elevation of tyrosine transaminase activity within 2 hr.6. The observations suggest that activity of vagal cholinergic nerves produces an RNA-dependent induction of hepatic tyrosine transaminase through a process requiring cholinergic-receptor stimulation. Intermittent activity of this vagal cholinergic system may contribute to the regulation of the daily rhythm in this enzyme.

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“…These diurnal variations are found in such diverse phenomena as metabolic activity (Bahorsky & Bernardis, 1967), motor and e.e.g. activity (Holmquest, Retiene & Lipscomb, 1966;Koella & Czieman, 1966;Mount & Willmott, 1967), and synthetic, enzymatic and catabolic processes (Min, Jones & Flink, 1966;Rapoport, Feigin, Bruton & Biesel, 1966;Civen, Ulrich, Trimmer & Brown, 1967;Wurtman, Chou & Rose, 1967).…”

Section: Introductionmentioning

confidence: 99%

Circadian rhythms in rat mid‐brain and caudate nucleus biogenic amine levels

Friedman¹,

Walker²

1968

The Journal of Physiology

156

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SUMMARY1. The circadian rhythms of rectal temperature and biogenic amine levels in mid-brain and caudate nucleus have been measured in normal and adrenalectomized rats adapted to and maintained under fixed illumination cycle.2. Rectal temperature reaches a peak value between 24.00 hr and 06.00 hr during the dark phase of the illumination cycle at a time when motor activity is maximal. In adrenalectomized rats, the pattern is similar but the peak is significantly lower.3. Highest histamine levels in the caudate nucleus and mid-brain of normal and adrenalectomized rats are found at the time when body temperature and motor activity is maximal.4. Similarly, caudate nucleus and mid-brain noradrenaline levels reach their peak during the dark phase of the illumination cycle. These levels are significantly different from those found during the light phase of the illumination cycle. The rise in noradrenaline in the mid-brain of adrenalectomized rats, however, was not significant.5. Peak 5-hydroxytryptamine (5-HT) levels in the caudate nucleus of normal rats and the mid-brain of adrenalectomized rats were found to be 12 hr out of phase with peak values obtained for other parameters that were measured.6. The significance ofthese circadian rhythms in relation to states of sleep and wakefulness, general metabolism, and motor activity is discussed.

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Circadian Rhythms of Liver Enzymes and Their Relationship to Enzyme Induction

Cited by 97 publications

References 11 publications

Principles for circadian orchestration of metabolic pathways

Principles for circadian orchestration of metabolic pathways

Cholinergic regulation of hepatic tyrosine transaminase activity

Circadian rhythms in rat mid‐brain and caudate nucleus biogenic amine levels

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