Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription

Raspé, Eric; Duez, Hélène; Mansén, Anethe; Fontaine, Coralie; Fiévet, Catherine; Fruchart, Jean Charles; Vennström, Björn; Staels, Bart

doi:10.1194/jlr.m200386-jlr200

Cited by 164 publications

(121 citation statements)

References 46 publications

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“…Defects in adipocyte differentiation were also seen in the absence of REV-ERBα, an upstream regulator of _ã~äN transcription (Wang and Lazar, 2008). Additionally, REV-ERBα represses lipid metabolism by binding to an AGGTAC motif in the promoter region of ^éç`Jfff (Raspe et al, 2002). In skeletal muscle, RORα regulates lipid homeostasis via direct activation of carnitine palmitoyltransferase 1 (`mqN), involved in fatty acid oxidation, and caveolin-3 (Lau et al, 2004).…”

Section: Circadian Control Of Metabolismmentioning

confidence: 99%

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

Kovac

Husse

Oster

2009

Molecules and Cells

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The cyclic environmental conditions brought about by the 24 h rotation of the earth have allowed the evolution of endogenous circadian clocks that control the temporal alignment of behaviour and physiology, including the uptake and processing of nutrients. Both metabolic and circadian regulatory systems are built upon a complex feedback network connecting centres of the central nervous system and different peripheral tissues. Emerging evidence suggests that circadian clock function is closely linked to metabolic homeostasis and that rhythm disruption can contribute to the development of metabolic disease. At the same time, metabolic processes feed back into the circadian clock, affecting clock gene expression and timing of behaviour. In this review, we summarize the experimental evidence for this bimodal interaction, with a focus on the molecular mechanisms mediating this exchange, and outline the implications for clock-based and metabolic diseases.

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Section: Circadian Control Of Metabolismmentioning

confidence: 99%

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

Kovac

Husse

Oster

2009

Molecules and Cells

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“…Apoa1 has an important role in the formation of nascent HDL particles and apolipoprotein-mediated cholesterol efflux in mice (18,19). Furthermore, Rev-erb␣ has also been shown to regulate the expression of the ApoC-III gene that plays a key role in maintaining serum triglyceride levels (20,21). The inter-relationship between Rev-erb␤ and lipid metabolism has not been investigated.…”

Section: And 8 and References Therein)mentioning

confidence: 99%

“…For example, the NR1D subfamily of orphan receptors regulate the expression of ApoC-III (20,21), a major component of triglyceride-rich remnant lipoprotein and associated with hypertriglyceridemia (37). In addition, Rev-erb␣ Ϫ/Ϫ mice have elevated levels of ApoC-III and very low density lipoprotein triglycerides.…”

Section: Figmentioning

confidence: 99%

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Ramakrishnan

Lau

Burke

et al. 2005

Journal of Biological Chemistry

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Rev-erb␤ is an orphan nuclear receptor that selectively blocks trans-activation mediated by the retinoic acid-related orphan receptor-␣ (ROR␣). ROR␣ has been implicated in the regulation of high density lipoprotein cholesterol, lipid homeostasis, and inflammation. Reverb␤ and ROR␣ are expressed in similar tissues, including skeletal muscle; however, the pathophysiological function of Rev-erb␤ has remained obscure. We hypothesize from the similar expression patterns, target genes, and overlapping cognate sequences of these nuclear receptors that Rev-erb␤ regulates lipid metabolism in skeletal muscle. This lean tissue accounts for >30% of total body weight and 50% of energy expenditure. Moreover, this metabolically demanding tissue is a primary site of glucose disposal, fatty acid oxidation, and cholesterol efflux. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. We utilize ectopic expression in skeletal muscle cells to understand the regulatory role of Rev-erb␤ in this major mass peripheral tissue. Exogenous expression of a dominant negative version of mouse Rev-erb␤ decreases the expression of many genes involved in fatty acid/lipid absorption (including Cd36, and Fabp-3 and -4). Interestingly, we observed a robust induction (>15-fold) in mRNA expression of interleukin-6, an "exerciseinduced myokine" that regulates energy expenditure and inflammation. Furthermore, we observed the dramatic repression (>20-fold) of myostatin mRNA, another myokine that is a negative regulator of muscle hypertrophy and hyperplasia that impacts on body fat accumulation. This study implicates Rev-erb␤ in the control of lipid and energy homoeostasis in skeletal muscle. In conclusion, we speculate that selective modulators of Rev-erb␤ may have therapeutic utility in the treatment of dyslipidemia and regulation of muscle growth. Members of the nuclear receptor (NR)1 superfamily bind to specific DNA elements and function as transcriptional regulators (1, 2). In addition to the ligand-activated NRs, many members within this superfamily have no known ligand, and are referred to as "orphan NRs" (3). The orphan receptor Rev-erb␤ (NR1D2, also known as Rev-erb␣-related receptor, RVR) belongs to the family of "Reverbs" that also contain Rev-erb␣ (4, 5). The primary structure of these two receptors together with retinoic acid-related orphan receptor-␣ (ROR␣) and the Drosophila orphan receptor, E75A, is very similar especially in the DNA-binding domain and the putative ligand-binding domain (6).Two Rev-erb␤ genes have been identified; Rev-erb␤1 and Rev-erb␤2, which are alternatively spliced products of the Reverb␤ gene (7). The mRNA expression data shows that Rev-erb␤ is abundantly expressed in most tissues, although higher levels of expression are observed in skeletal muscle, brain, kidney, and liver (Refs. 4 and 8 and references therein).Rev-erb␣, Rev-erb␤, and ROR bind as monomers to the nuclear receptor half-site motif, PuGGTCA flanked 5Ј by an ATrich sequence ((A/T) 6 PuGGTCA). Although...

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“…Rev-erb␣ competes with ROR␣, 2 liver X receptor ␣ (LXR␣), and peroxisome proliferator-activated receptor ␣ (PPAR␣) for these response elements and has opposing effects on transcription (11)(12)(13). In several instances, Rev-erb␣ DR2 overlaps the TATA box (14,15), which suggests the possibility that Rev-erb␣ is a component of a basal repressive transcription complex.…”

mentioning

confidence: 99%

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

Chandra

Mahajan

Saini

et al. 2013

Journal of Biological Chemistry

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Background: Transcriptional modulation of IL10, a cytokine that blocks phagolysosome maturation, is not well understood. Results: This study demonstrates human IL10 gene repression by direct binding of Rev-erb␣ on Rev-DR2 in the proximal promoter. Conclusion: Rev-erb␣ binds to IL10 proximal promoter, represses expression, and impedes Mycobacterium tuberculosis in human macrophages. Significance: This study provides rationale to target Rev-erb␣ as a therapeutic intervention that might support host defense in tuberculosis.Nuclear receptors modulate macrophage effector functions, which are imperative for clearance or survival of mycobacterial infection. The adopted orphan nuclear receptor Rev-erb␣ is a constitutive transcriptional repressor as it lacks AF2 domain and was earlier shown to be present in macrophages. In the present study, we highlight the differences in the relative subcellular localization of Rev-erb␣ in monocytes and macrophages. The nuclear localization of Rev-erb␣ in macrophages is subsequent to monocyte differentiation. Expression analysis of Rev-erb␣ elucidated it to be considerably more expressed in M1 phenotype in comparison with M2. Rev-erb␣ overexpression augments antimycobacterial properties of macrophage by keeping IL10 in a basal repressed state. Further, promoter analysis revealed that IL10 promoter harbors a Rev-erb␣ binding site exclusive to humans and higher order primates and not mouse, demonstrating a species barrier in its functionality. This direct gene repression is mediated by recruitment of co-repressors NCoR and HDAC3. In addition, our data elucidate that its overexpression reduced the survival of intracellular pathogen Mycobacterium tuberculosis by enhancing phagosome lysosome maturation, an event resulting from IL10 repression. Thus, these findings suggest that Rev-erb␣ bestows protection against mycobacterial infection by direct gene repression of IL10 and thus provide a novel target in modulating macrophage microbicidal properties.Macrophages are immune system sentinels with a major role to play in both innate and adaptive immunity. They are the key effectors in antimicrobial defense, atherogenesis, autoimmunity, and many other inflammatory diseases (1). Although the activation, function, classification, and plasticity of these cells have been studied extensively with regard to cellular signaling, the cytokine environment, and surface, cellular, or secretory markers, studies of the underlying molecular mechanism have mostly addressed NF-B (2). Similarly, modulation of macrophage function and alteration of disease pathology by small molecules such as heme, lipids, or drugs such as rifampicin are well understood at the translational level of the effectors (3, 4), but the transcriptional mechanism involving interactions of these ligands with transcriptional molecules and the resulting expression patterns have not been investigated.This study focuses on Rev-erb␣, an adopted orphan nuclear receptor that belongs to the steroid/thyroid hormone receptor superfamily and is a known ...

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Identification of Rev-erbα as a physiological repressor of apoC-III gene transcription

Cited by 164 publications

References 46 publications

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

A Time to Fast, a Time to Feast: The Crosstalk between Metabolism and the Circadian Clock

Rev-erbβ Regulates the Expression of Genes Involved in Lipid Absorption in Skeletal Muscle Cells

Human IL10 Gene Repression by Rev-erbα Ameliorates Mycobacterium tuberculosis Clearance

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