Abstract
The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues. Circadian expression of the Elovl3 gene in the liver is perturbed in mutant CLOCK mice but persists in mice with severe hepatic dysfunction. A reliance on an intact clock, combined with the refractoriness to liver decompensation and the finding of a robust sexually dimorphic pattern of expression, evince a particularly complex mode of transcriptional control. The Elovl3 gene upstream region was repressed by RevErbalpha and activated by sterol-regulatory element binding protein-1 (SREBP1) transcription factors. We propose that the temporal coordination of RevErbalpha and SREBP1 activities integrates clock and nutrition signals to drive a subset of oscillatory transcripts in the liver. Proteolytic activation of SREBP1 is circadian in the liver, and because the cycle of SREBP1 activation was reversed after restricting meals to the inactive phase of the day, this factor could serve as an acute sensor of nutritional state. SREBP1 regulates many known lipogenic and cholesterogenic circadian genes; hence, our results could explain how feeding can override brain-derived entraining signals in the liver. This mechanism would permit a rapid adjustment in the sequence of key aspects of the absorptive and postabsorptive phases in the liver.
Highlights
The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues
Experimental procedures involving the A-ZIP/F-1 fatless strain of transgenic mice and all related supplemental data can be viewed at the following URL: http://neuroscience.nih. gov/Baler/CIG30ms/supplementaldata.pdf. (In accordance with the Mouse Nomenclature Committee, the assigning symbol for the mouse gene cold-inducible glycoprotein of 30 kDa (Cig30) is changed to Elovl3.) For restricted feeding experiments, C57BL/6 male mice were entrained to a 12 h/12 h photoperiod for 2 weeks
Because we have shown in this study, for the first time, that a similar paradigm shifts the sterol-regulatory element binding protein-1 (SREBP1) activation cycle and Elovl3 mRNA acrophase by z9 h (Fig. 3), these observations are consistent with the hypothesis that the coordinated actions of RevErba and SREBP1 are ideally positioned to drive the observed rhythm in Elovl3 expression, and likely many other late-night-peaking genes, in the liver
Summary
The ELOVL3 protein is a very long-chain fatty acid elongase found in liver, skin, and brown adipose tissues. Steady-state levels of Elovl mRNA follow a robust circadian profile in the liver, according to a recent transcriptome analysis [4] This rhythm, which appears to be perturbed in the CLOCK mutant mouse [4], displays a late-night acrophase, suggesting that if there is a link to the circadian BMAL/CLOCK pathway, it is most likely indirect, because BMAL/CLOCK activity peaks during the second half of the light phase [5]. This article is available online at http://www.jlr.org the nocturnal induction of the Elovl gene displayed the largest amplitude of day/night rhythmic expression between the two time points selected, among all the genes present in the microarray This observation suggested that at least some rhythmic BMAL/CLOCK activity is present in A-ZIP/F-1 mice and that Elovl represents a potential downstream clock-controlled gene
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