Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 108, Issue 12, Pages 4794-4799Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1002862108
Keywords
circadian clock; liver lipid metabolism; nuclear receptors
Categories
Funding
- Swiss National Science Foundation
- National Center of Competence in Research Program Frontiers in Genetics
- Cantons of Geneva and Vaud
- Louis Jeantet Foundation of Medicine
- Bonizzi-Theler-Stiftung
- Sixth European Framework Project EUCLOCK
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In mammals, many aspects of metabolism are under circadian control. At least in part, this regulation is achieved by core-clock or clock-controlled transcription factors whose abundance and/or activity oscillate during the day. The clock-controlled proline- and acidic amino acid-rich domain basic leucine zipper proteins D-site-binding protein, thyrotroph embryonic factor, and hepatic leukemia factor have previously been shown to participate in the circadian control of xenobiotic detoxification in liver and other peripheral organs. Here we present genetic and biochemical evidence that the three proline- and acidic amino acid-rich basic leucine zipper proteins also play a key role in circadian lipid metabolism by influencing the rhythmic expression and activity of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPAR alpha). Our results suggest that, in liver, D-site-binding protein, hepatic leukemia factor, and thyrotroph embryonic factor contribute to the circadian transcription of genes specifying acyl-CoA thioesterases, leading to a cyclic release of fatty acids from thioesters. In turn, the fatty acids act as ligands for PPAR alpha, and the activated PPAR alpha receptor then stimulates the transcription of genes encoding proteins involved in the uptake and/or metabolism of lipids, cholesterol, and glucose metabolism.
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