Identification of Reverbα as a Novel RORα Target Gene

Delerive, Philippe; Chin, William W.; Suen, Chen S.

doi:10.1074/jbc.m202979200

Cited by 53 publications

(48 citation statements)

References 54 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Recent data have provided evidence for a crosstalk between REV-ERB-alpha and RORalpha1 in the modulation of the APOC3 promoter. 24 The APOC3 gene promoter and a distal regulatory region acts as a common enhancer for the three genes of the apolipoprotein cluster on 11q23 (APOC3, APOA1, and APOA4 [MIM 107690]), which could explain the decrease in APOA1 transactivation in the staggerer mouse. 25 The role of RORa in lipid regulation in skeletal muscle has also been implicated and thereby suggesting that RORa could be a critical regulator of energy homeostasis in this major mass of lean tissue.…”

Section: Discussionmentioning

confidence: 99%

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

et al. 2005

View full text Add to dashboard Cite

We have identified a family comprising a mother and two children with idiopathic and profound obesity body mass index (BMI) 41 -49 kg/m 2 . The three family members carry a balanced reciprocal chromosome translocation t(4;15). We present here the clinical features of the affected individuals as well as the physical mapping and cloning of the chromosomal breakpoints. A detailed characterisation of the chromosomal breakpoints at chromosomes 4 and 15 revealed that the translocation is almost perfectly balanced with a very short insertion/deletion. The chromosome 15 breakpoint is positioned in intron 1 of the RAR-related orphan receptor A isoform 1 (RORa1) and the chromosome 4 breakpoint is positioned 133 kb telomeric to the transcriptional start of the unc-5 homolog B (UNC5C) and 154 kb centromeric of the transcriptional start of the pyruvate dehydrogenase (lipoamide) alpha 2 (PDHA2). The rearrangement creates a fusion gene, which includes the RORa1 exon 1 and UNC5C that is expressed in frame in adipocytes from the affected patients. We also show that this transcript is translated into a protein. From previous reports, it is shown that RORa1 is implicated in the regulation of adipogenesis and lipoprotein metabolism. We hypothesise that the obesity in this family is caused by (i) haploinsufficiency for RORa1 or, (ii) a gain of function mechanism mediated by the RORa1 -UNC5C fusion gene.

show abstract

Section: Discussionmentioning

confidence: 99%

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

et al. 2005

View full text Add to dashboard Cite

show abstract

“…40 Very recently, it has been shown that ROR␣1 induces Rev-erb␣ gene expression. 41 Rev-erb␣, in turn, is known to inter- act with the nuclear receptor corepressor N-CoR. 42,43 It is then possible that in prostate cancer cells the activated ROR␣1 might also reclute specific corepressors to inhibit the expression of the 5-LOX gene.…”

Section: Discussionmentioning

confidence: 99%

Activation of the orphan nuclear receptor RORα counteracts the proliferative effect of fatty acids on prostate cancer cells: Crucial role of 5‐lipoxygenase

Moretti

Marelli

Sala

et al. 2004

Intl Journal of Cancer

View full text Add to dashboard Cite

show abstract

“…Whereas ROR activates gene transcription, Rev-erb␣ and Rev-erb␤ mediate transcriptional repression, and can repress trans-activation mediated by ROR (6, 9 -12). The inter-relationship between these nuclear receptors is underscored by the evidence that demonstrates ROR␣ trans-activates the Rev-erb␣ promoter (13).…”

Section: And 8 and References Therein)mentioning

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

View full text Add to dashboard Cite

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...

show abstract

Identification of Reverbα as a Novel RORα Target Gene

Cited by 53 publications

References 54 publications

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

RAR-related orphan receptor A isoform 1 (RORa1) is disrupted by a balanced translocation t(4;15)(q22.3;q21.3) associated with severe obesity

Activation of the orphan nuclear receptor RORα counteracts the proliferative effect of fatty acids on prostate cancer cells: Crucial role of 5‐lipoxygenase

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

Contact Info

Product

Resources

About