Proc Natl Acad Sci USA; co-auth group Wahli

Proc Natl Acad Sci U S A. 2011 Mar 7. [Epub ahead of print]

Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator-activated receptor {alpha} (PPAR{alpha}) activity.

Gachon F, Leuenberger N, Claudel T, Gos P, Jouffe C, Fleury Olela F, de Mollerat du Jeu X, Wahli W, Schibler U.

Department of Molecular Biology, National Center of Competence in Research “Frontiers in Genetics,” Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland.

Abstract

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 α (PPARα). 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 PPARα, and the activated PPARα receptor then stimulates the transcription of genes encoding proteins involved in the uptake and/or metabolism of lipids, cholesterol, and glucose metabolism.

PMID: 21383142 [PubMed - as supplied by publisher]