Elovl3: a model gene to dissect homeostatic links between the circadian clock and nutritional status.
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.
Anzulovich
Ana
A
Unit on Temporal Gene Expression, Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, National Institutes of Health, Bethesda, MD 20892, USA.
Mir
Alain
A
Brewer
Michelle
M
Ferreyra
Gabriela
G
Vinson
Charles
C
Baler
Ruben
R
D000123:Acetyltransferases; D000818:Animals; D001483:Base Sequence; D056926:CLOCK Proteins; D002460:Cell Line; D002940:Circadian Rhythm / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000081031:Fatty Acid Elongases; D005260:Female; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D009752:Nutritional Status / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012727:Sex Characteristics; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D018076:DNA, Complementary; D004268:DNA-Binding Proteins; C000630953:ELOVL3 protein, human; C000630960:Elovl3 protein, mouse; D008565:Membrane Proteins; C064353:NR1D1 protein, human; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D018160:Receptors, Cytoplasmic and Nuclear; D011994:Recombinant Proteins; D051779:Sterol Regulatory Element Binding Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000123:Acetyltransferases; D000081031:Fatty Acid Elongases; D056926:CLOCK Proteins; C538943:CLOCK protein, human; C538944:Clock protein, mouse