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And Acidic Amino Acid-Rich Basic Leucine Zipper Proteins Modulate Peroxisome Proliferator- Activated Receptor Α (Pparα) Activity

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And Acidic Amino Acid-Rich Basic Leucine Zipper Proteins Modulate Peroxisome Proliferator- Activated Receptor Α (Pparα) Activity Proline- and acidic amino acid-rich basic leucine zipper proteins modulate peroxisome proliferator- activated receptor α (PPARα) activity Frédéric Gachona,b,1, Nicolas Leuenbergerc,2, Thierry Claudeld, Pascal Gosa, Céline Jouffeb, Fabienne Fleury Olelaa, Xavier de Mollerat du Jeue, Walter Wahlic, and Ueli Schiblera,1 aDepartment of Molecular Biology, National Center of Competence in Research “Frontiers in Genetics,” Sciences III, University of Geneva, CH-1211 Geneva 4, Switzerland; bDepartment of Pharmacology and Toxicology, University of Lausanne, CH-1005 Lausanne, Switzerland; cCenter for Integrative Genomics, National Center of Competence in Research “Frontiers in Genetics,” University of Lausanne, CH-1015 Lausanne, Switzerland; dLaboratory of Experimental and Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Medicine, Medical University Graz, A-8036 Graz, Austria; and eLife Technologies, Carlsbad, CA 92008 Edited by Steven L. McKnight, University of Texas Southwestern, Dallas, TX, and approved February 4, 2011 (received for review April 7, 2010) In mammals, many aspects of metabolism are under circadian leucine zipper (PAR bZip) proteins, D-site-binding protein control. At least in part, this regulation is achieved by core-clock (DBP), thyrotroph embryonic factor (TEF), and hepatic leuke- or clock-controlled transcription factors whose abundance and/or mia factor (HLF), are examples of such output mediators (for activity oscillate during the day. The clock-controlled proline- review, see ref. 7). Mice deficient of only one or two members and acidic amino acid-rich domain basic leucine zipper proteins of the PAR bZip gene family display rather mild phenotypes, D-site-binding protein, thyrotroph embryonic factor, and hepatic suggesting that the three members execute partially redundant leukemia factor have previously been shown to participate in functions. However, mice deficient of all three PAR bZip genes the circadian control of xenobiotic detoxification in liver and other (henceforth called PAR bZip 3KO mice) have a dramatically peripheral organs. Here we present genetic and biochemical evi- reduced life span due to epileptic seizures (8) and impaired dence that the three proline- and acidic amino acid-rich basic xenobiotic detoxification (9). leucine zipper proteins also play a key role in circadian lipid meta- Genome-wide transcriptome profiling of wild-type and PAR bolism by influencing the rhythmic expression and activity of the bZip 3KO mice has revealed differentially expressed genes nuclear receptor peroxisome proliferator-activated receptor α involved in lipid metabolism, many of which are targets of the (PPARα). Our results suggest that, in liver, D-site-binding protein, nuclear receptor PPARα. Here we present evidence for a pathway hepatic leukemia factor, and thyrotroph embryonic factor contri- in which PAR bZip transcription factors connect the accumula- bute to the circadian transcription of genes specifying acyl-CoA tion and activity of PPARα to circadian oscillators in liver. thioesterases, leading to a cyclic release of fatty acids from thioe- sters. In turn, the fatty acids act as ligands for PPARα, and the Results activated PPARα receptor then stimulates the transcription of Pparα Expression in PAR bZip 3KO Mice. Genome-wide microarray genes encoding proteins involved in the uptake and/or metabolism transcriptome profiling studies with liver RNA from wild-type of lipids, cholesterol, and glucose metabolism. and PAR bZip 3KO mice revealed differentially expressed genes involved in xenobiotic detoxification (9) and lipid metabolism circadian clock ∣ liver lipid metabolism ∣ nuclear receptors (this paper). The latter included Pparα, a gene specifying a nuclear receptor that is well known as a regulator of lipid n mammals, energy homeostasis demands that anabolic and metabolism, and many PPARα target genes (10) (Fig. S1A). We Icatabolic processes are coordinated with alternating periods validated the reduced accumulation of Pparα mRNA and tran- of feeding and fasting. There is increasing evidence that inputs scripts issued by PPARα target genes by using quantitative from the circadian clock are required in addition to acute regu- RT-PCR analysis (Fig. 1 A and B and Fig. S1B). The examined latory mechanisms to adapt metabolic functions to an animal’s PPARα target genes include Cyp4a10 and Cyp4a14, encoding daily needs. For example, mice with disrupted hepatocyte clocks enzymes involved in FA ω-oxidation (whose expression is strongly display a hypoglycemia during the postabsorptive phase, suppo- reduced in Pparα KO mice, see Fig. S2A), and genes specifying sedly because hepatic gluconeogenesis and glucose delivery into enzymes involved in FA β-oxidation (Fig. S1B). PPARα has also the bloodstream are dysregulated in these animals (1). been shown to activate transcription from its own promoter, when The regulation of lipid metabolism is also governed by an activated by PPARα agonists (11). To evaluate the relevance of interaction between acute and circadian regulatory mechanisms, this feed-forward loop in circadian Pparα transcription, we com- and the three peroxisome proliferator-activated receptors pared the temporal expression of Pparα pre-mRNA in the liver of (PPARα,PPARβ/δ, and PPARγ) play particularly important roles wild-type mice with that of nonproductive pre-mRNA transcripts in these processes (2). Among them, PPARα acts as a molecular issued by the disrupted Pparα alleles in Pparα KO mice (12). As sensor of endogenous fatty acids (FAs) and regulates the tran- scription of genes involved in lipid uptake and catabolism. More- over, it accumulates according to a daily rhythm and reaches Author contributions: F.G., N.L., T.C., X.d.M.d.J., W.W., and U.S. designed research; F.G., N.L., T.C., P.G., C.J., and F.F.O. performed research; X.d.M.d.J. contributed new reagents/ maximal levels around the beginning of feeding time (3, 4). For analytic tools; F.G., N.L., T.C., W.W., and U.S. analyzed data; and F.G., W.W., and U.S. wrote liver and many other peripheral tissues, feeding–fasting rhythms the paper. are the most dominant zeitgebers (timing cues) (5, 6). This ob- The authors declare no conflict of interest. servation underscores the importance of the cross-talk between This article is a PNAS Direct Submission. metabolic and circadian cycles. 1To whom correspondence may be addressed. E-mail: [email protected] or Circadian oscillators in peripheral tissues can participate in the [email protected]. control of rhythmic metabolism through circadian transcription 2Present address: Swiss Laboratory for Doping Analysis, CH-1066 Epalinges, Switzerland. factors, which in turn regulate the cyclic transcription of metabo- This article contains supporting information online at www.pnas.org/lookup/suppl/ lically relevant downstream genes. The three PAR-domain basic doi:10.1073/pnas.1002862108/-/DCSupplemental. 4794–4799 ∣ PNAS ∣ March 22, 2011 ∣ vol. 108 ∣ no. 12 www.pnas.org/cgi/doi/10.1073/pnas.1002862108 Downloaded by guest on September 26, 2021 depicted in Fig. 1C, the circadian expression was indeed dam- that PPARα had a higher activity in the former animals than in pened in these animals, suggesting that PPARα contributed to the latter. the rhythmic transcription of its own gene. Therefore, PAR bZip transcription factors may have activated Pparα transcription PAR bZip Transcription Factors May Stimulate PPARα Activity Through α through an indirect mechanism, for example, by promoting the the Production of PPAR Ligands. FAs generated by the metabolism α of dietary lipids or de novo synthesis are the best known natural cyclic generation of PPAR ligands. α – Unexpectedly, hepatic PPARα protein accumulation was ligands for PPAR (15 17). In liver, FAs can be produced through higher in PAR bZip 3KO mice as compared to wild-type mice, the hydrolysis of acyl-CoA esters by acyl-CoA thioesterases (ACOTs) (18) and through the hydrolysis of lipids in lipoproteins in spite of the lower mRNA levels in the former (Fig. 1D). How- by lipoprotein lipases (LPLs) (19). Interestingly, members of both ever, nuclear receptors can be destabilized in a ligand-dependent of these two enzyme families have been reported to accumulate manner (for review, see ref. 13). Hence, the higher protein to according to a daily rhythm in the liver (20–22), and our genome- mRNA level in hepatocytes of PAR bZip 3KO mice could indi- wide transcriptome profiling experiments suggested that the cate that in these animals PPARα was less active and therefore mRNAs for these enzymes were expressed at reduced levels in more stable than in the liver of wild-type mice. To examine this PAR bZip 3KO mice. As shown in Fig. 2B, the accumulation conjecture, we measured hepatic PPARα protein and mRNA of transcripts specifying ACOTs displayed temporal expression accumulation, 4 h after an intraperitoneal injection of the syn- patterns expected for direct PAR bZip target genes and was thetic PPARα ligand WY14643 into PAR bZip 3KO mice. As indeed blunted in PAR bZip 3KO mice. The Acot genes are all shown in Fig. 1E and Fig. S3, the injection of the PPARα ligand located on a 120 kb cluster on mouse chromosome 12, and a led to a decrease of the protein to mRNA ratio, in keeping with perfect PAR bZip DNA binding sequence is located between Acot1 Acot4 A the model of Kamikaze activators postulated by Thomas and and (Fig. 2 ). At least in vitro, this sequence binds α PAR bZip in a diurnal manner (Fig. 2A), which could explain the Tyers (14). The lower PPAR protein to mRNA ratio in wild- Lpl type as compared to PAR bZip 3KO mice may therefore indicate rhythmic expression of these genes. However, the phase of transcript accumulation was found to be delayed by 12 h when compared to that of Acot expression, and we suspected that A PAR bZip proteins regulate Lpl transcription via an indirect mechanism. Interestingly, Acot and Lpl reached maximal concen- trations at ZT12 and ZT24, respectively, suggesting a bimodal metabolism of FAs in mouse liver: hydrolysis of acyl-CoAs at the day–night transition and hydrolysis of lipids in lipoproteins at the night–day transition.
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