Regulation of Bile Acid Synthesis by the Nuclear Receptor Rev-erbα

Duez, Hélène; Veen, Jelske N. van der; Duhem, Christian; Pourcet, Benoît; Touvier, Thierry; Fontaine, Coralie; Derudas, Bruno; Baugé, Eric; Havinga, Rick; Bloks, Vincent W.; Wolters, Henk; Sluijs, Fjodor H. van der; Vennström, Björn; Kuipers, Folkert; Staels, Bart

doi:10.1053/j.gastro.2008.05.035

Cited by 178 publications

(151 citation statements)

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“…The mammalian E4BP4 has been implicated in the circadian regulation of a number of circadian output genes, including Per2 (63), Cyp7A (28), and Cyp3A4 (64), suggesting that E4BP4 functions as a mediator of the circadian clock to control its output gene expression. In this study, we discovered a novel link between the circadian protein E4BP4-dependent transcription repression and the circadian oscillation of a key metabolic regulator in liver metabolism.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…Genetic loss-of-function and gain-of-function experiments provided evidence that REV-ERBa is involved in the circadian modulation of SREBP activity, and hence the daily expression of SREBP target genes involved in cholesterol and lipid metabolism (Le Martelot et al, 2009). In addition, REVERBa also participates in the rhythmic expression of cholesterol-7a-hydroxylase (CYP7A1), a rate-limiting enzyme that converts cholesterol to bile acids (Duez et al, 2008;Le Martelot et al, 2009). Lipid homeostasis is also perturbed by disruption of clockcontrolled genes downstream of the core clock machinery.…”

Section: Role Of Clock Components In Lipid Metabolismmentioning

confidence: 99%

Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals

Jha

Challet

Kalsbeek

2015

Molecular and Cellular Endocrinology

179

125

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a b s t r a c tMost aspects of energy metabolism display clear variations during day and night. This daily rhythmicity of metabolic functions, including hormone release, is governed by a circadian system that consists of the master clock in the suprachiasmatic nuclei of the hypothalamus (SCN) and many secondary clocks in the brain and peripheral organs. The SCN control peripheral timing via the autonomic and neuroendocrine system, as well as via behavioral outputs. The sleepewake cycle, the feeding/fasting rhythm and most hormonal rhythms, including that of leptin, ghrelin and glucocorticoids, usually show an opposite phase (relative to the lightedark cycle) in diurnal and nocturnal species. By contrast, the SCN clock is most active at the same astronomical times in these two categories of mammals. Moreover, in both species, pineal melatonin is secreted only at night. In this review we describe the current knowledge on the regulation of glucose and lipid metabolism by central and peripheral clock mechanisms. Most experimental knowledge comes from studies in nocturnal laboratory rodents. Nevertheless, we will also mention some relevant findings in diurnal mammals, including humans. It will become clear that as a consequence of the tight connections between the circadian clock system and energy metabolism, circadian clock impairments (e.g., mutations or knock-out of clock genes) and circadian clock misalignments (such as during shift work and chronic jet-lag) have an adverse effect on energy metabolism, that may trigger or enhancing obese and diabetic symptoms.

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“…Bile acid synthesis and CYP7A1 expression exhibit a strong circadian rhythm, peaking at the onset of dark and decreasing in the light cycle (12)(13)(14)(15). It has been reported that peroxisome proliferator-activated receptor ␣, DEC1/2, and E4BP4 are negative regulators, whereas Rev-erb␣ and D-site binding protein are positive regulators of circadian rhythm of CYP7A1 (16,17). Rev-erb␣ is a negative clock gene that stimulates CYP7A1 via inhibiting SHP (small heterodimer partner) and E4BP4, the negative regulators of CYP7A1 (17).…”

mentioning

confidence: 99%

“…It has been reported that peroxisome proliferator-activated receptor ␣, DEC1/2, and E4BP4 are negative regulators, whereas Rev-erb␣ and D-site binding protein are positive regulators of circadian rhythm of CYP7A1 (16,17). Rev-erb␣ is a negative clock gene that stimulates CYP7A1 via inhibiting SHP (small heterodimer partner) and E4BP4, the negative regulators of CYP7A1 (17). In Clock gene mutant mice, the circadian rhythm of CYP7A1 is enhanced, but that of CYP8B1 is diminished (16).…”

mentioning

confidence: 99%

Retinoic Acid-related Orphan Receptor α Regulates Diurnal Rhythm and Fasting Induction of Sterol 12α-Hydroxylase in Bile Acid Synthesis

Pathak

Chiang

2013

Journal of Biological Chemistry

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Background: Sterol 12␣-hydroxylase catalyzes cholic acid synthesis. ROR␣ is a cholesterol-activated and fasting-induced nuclear receptor and core clock gene. Results: Upon fasting, glucagon/PKA phosphorylated and stabilized ROR␣ protein to induce CYP8B1 and diurnal rhythm. Conclusion: ROR␣ is a key regulator of CYP8B1 that regulates bile acid and cholesterol homeostasis. Significance: Antagonizing ROR␣ activity may be a therapeutic strategy for treating non-alcoholic fatty liver disease and diabetes.

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Regulation of Bile Acid Synthesis by the Nuclear Receptor Rev-erbα

Cited by 178 publications

References 56 publications

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

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

Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals

Retinoic Acid-related Orphan Receptor α Regulates Diurnal Rhythm and Fasting Induction of Sterol 12α-Hydroxylase in Bile Acid Synthesis

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