Circadian expression of <i>FGF21</i> is induced by PPARα activation in the mouse liver

Oishi, Katsutaka; Uchida, Daisuke; Ishida, Norio

doi:10.1016/j.febslet.2008.09.046

Cited by 81 publications

(71 citation statements)

References 22 publications

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“…In mice, the PPAR␣ agonist bezafibrate induces FGF21 expression in a circadian manner (30 ). Our 24-h profiling analysis of circulating FGF21 in fasting mice also shows a circadian pattern of FGF21 reminiscent of that in humans.…”

Section: Discussionmentioning

confidence: 69%

Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

et al. 2011

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Section: Discussionmentioning

confidence: 69%

Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

et al. 2011

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“…Studies have suggested that FGF21 expression is regulated in a circadian manner (35), leading to the possibility that ROR␣ and REV-ERB␣ may be contributing to its circadian pattern of expression. The circadian rhythm is tightly coupled to metabolic regulation, and among several stimuli that can entrain the clock is food (36).…”

Section: Discussionmentioning

confidence: 99%

Regulation of FGF21 Expression and Secretion by Retinoic Acid Receptor-related Orphan Receptor α

Wang

Solt

Burris

2010

Journal of Biological Chemistry

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Fibroblast growth factor 21 (FGF21) is a hormone produced by fat and the liver that plays an important role in lipid metabolism. FGF21 expression is induced by peroxisome proliferatoractived receptor ␣ in response to physiological conditions requiring increased fatty acid oxidation. Retinoic acid receptorrelated receptor ␣ (ROR␣) is another nuclear receptor that plays a critical role in lipid metabolism as well as in regulation of the circadian rhythm. In this study we demonstrate that ROR␣ directly regulates the expression and secretion of FGF21. A canonical ROR response element was identified in the proximal promoter of the FGF21 gene and shown to exhibit functional activity. Overexpression of ROR␣ in HepG2 cells resulted in increased expression and secretion of FGF21. Suppression of ROR␣ expression caused a decrease in FGF21 expression and secretion, suggesting that ROR␣ contributes to the basal expression of FGF21. These data suggest that one mechanism by which ROR␣ regulates lipid metabolism may be by modulation of FGF21 secretion. Furthermore, this study identifies a clear link between ROR␣, a key regulator of the mammalian clock, and FGF21, an important hormone regulating glucose and lipid homeostasis.The regulation of lipid metabolism is tightly controlled and several nuclear hormone receptors (NHRs) 2 play an essential role in maintaining metabolic homeostasis. The retinoic acid receptor-related orphan receptors ROR␣ (NR1F1) and ROR␥ (NR1F3) have been implicated in metabolic pathways, energy homeostasis, and thymopoiesis. In addition, RORs regulate the expression of several components of the circadian clock and the expression of several downstream genes involved in metabolism.Like all NHRs, the RORs display a typical nuclear receptor domain structure consisting of four major functional domains: an amino-terminal (A/B) domain followed by a highly conserved DNA-binding domain, a hinge domain, and a carboxylterminal ligand-binding domain. RORs regulate gene expression by binding as monomers to specific "half-site" DNA response elements (ROREs) consisting of an AGGTCA sequence with a 5Ј AT-rich extension. RORs recruit coactivators resulting in constitutive activation of target gene transcription (1-3).ROR␣ has been shown to regulate several genes involved in lipid metabolism. Detailed examination of staggerer mice (ROR␣ sg/sg ) in which there is a frameshift and a premature stop codon, rendering ROR␣ inactive, have revealed significant alterations in lipid metabolism including low levels of total plasma cholesterol, triglycerides, and apolipoprotein CIII (4). ROR␣ directly regulates the expression of genes for both apoA1 and apoCIII (5, 6). Consistent with this phenotype, the staggerer mice are less susceptible to high fat diet-induced obesity and hepatic stetosis (7).ROR␥-deficient mice exhibit normal levels of plasma cholesterol and triglycerides (8). However, when crossed with the staggerer mouse, the ROR␣/␥-deficient mice present with hypoglycemia, suggesting a role for these receptors in the maintena...

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“…The Fgf21 mRNA is significantly induced by fasting but potently repressed by feeding (35,36). Although Fgf21 induction has been attributed to the PPAR␣-mediated activation in the adaptive response during fasting (35,36,54), the underlying mechanism for feeding-induced Fgf21 repression is unknown. To determine whether E4BP4 also plays a role in feeding-induced Fgf21 repression, we measured the E4bp4 mRNA and protein levels in the mouse liver tissues after fasting and ad libitum feeding for 24 h. Fasting, but not feeding, induced the expression of G6pase, Pepck, and Pgc1␣ in the mouse livers (Fig.…”

Section: Fgf21 Is a Circadian-regulatedmentioning

confidence: 99%

Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding

Tong

Muchnik

Chen

et al. 2010

Journal of Biological Chemistry

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Fibroblast growth factor 21 (FGF21) is a potent antidiabetic and triglyceride-lowering hormone whose hepatic expression is highly responsive to food intake. FGF21 induction in the adaptive response to fasting has been well studied, but the molecular mechanism responsible for feeding-induced repression remains unknown. In this study, we demonstrate a novel link between FGF21 and a key circadian output protein, E4BP4. Expression of Fgf21 displays a circadian rhythm, which peaks during the fasting phase and is anti-phase to E4bp4, which is elevated during feeding periods. E4BP4 strongly suppresses Fgf21 transcription by binding to a D-box element in the distal promoter region. Depletion of E4BP4 in synchronized Hepa1c1c-7 liver cells augments the amplitude of Fgf21 expression, and overexpression of E4BP4 represses FGF21 secretion from primary mouse hepatocytes. Mimicking feeding effects, insulin significantly increases E4BP4 expression and binding to the Fgf21 promoter through AKT activation. Thus, E4BP4 is a novel insulin-responsive repressor of FGF21 expression during circadian cycles and feeding.The mammalian circadian rhythm system plays a fundamental role in coordinating various physiological processes, which are manifested by a precise 24-h cycle and responsiveness to light or food cues (1-4). Recent genetic and biochemical studies of mammals, Drosophila, and bacteria have provided a general model of the circadian clock that is based on a transcriptional-translational feedback loop consisting of both positive and negative circadian clock proteins (1, 4). Besides controlling the core circadian oscillation loop, the clock proteins also actively participate in rhythmic expression of various output genes, which may account for the rhythmic activities in peripheral tissues (1, 3). As demonstrated in various microarray studies, genes important for gluconeogenesis, lipogenesis, and cholesterol synthesis are potential targets of clock proteins (5-8). Therefore, for drug administration and drug design, it becomes critical to understand how the cycling of individual metabolic genes is regulated in a 24-h rhythm (9, 10). E4BP4 (E4-binding protein 4), also called NFIL3, is a b-ZIP (basic leucine zipper) transcription factor initially identified as an IL-3-inducible factor in pro-B lymphocytes (11-13). The biological function of E4BP4 has been largely explored in the immune system, in which E4BP4 knock-out mice are defective in natural killer cell development and IgE class switch (14 -16). E4BP4 was first identified as a clock-controlled gene in mouse liver (17,18). Its mRNA and protein levels oscillate in a circadian fashion, which is anti-phase to DBP (D-site of albumin promoter-binding protein), another clock-controlled output gene (19). The mRNA of E4BP4 peaks at circadian time (CT) 2 0 and troughs at CT 12 (17,20). Although the role of E4BP4 in the mammalian circadian system is unclear, its homologue in Drosophila, vrille, serves as a key component of the core circadian network via a negative feedback loop (21-23). E...

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Circadian expression of FGF21 is induced by PPARα activation in the mouse liver

Cited by 81 publications

References 22 publications

Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

Circadian Rhythm of Circulating Fibroblast Growth Factor 21 Is Related to Diurnal Changes in Fatty Acids in Humans

Regulation of FGF21 Expression and Secretion by Retinoic Acid Receptor-related Orphan Receptor α

Transcriptional Repressor E4-binding Protein 4 (E4BP4) Regulates Metabolic Hormone Fibroblast Growth Factor 21 (FGF21) during Circadian Cycles and Feeding

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