Hormone receptor-like in 46


RORalpha, a mammalian homolog of HR46

The highest level of identity of human RORalpha1 is found in the presumptive DNA-binding domain (77%) of the Drosophila orphan receptor Hr46/DHR3. The similarity between RORalpha and Hr46 is higher within short amino and carboxy regions immediately adjacent to the zinc finger region. In addition, RORalpha and Hr46 share similar intron-exon boundaries delineating the amino and carboxy ends of the zinc fingers region, although the Hr46 gene has lost the intron separating the two exons encoding each zinc finger of RORalpha. The ligand binding domain of the Human and fly protein bear 31% identity. The amino acid sequence comparisons of RORalpha show distinct amino-terminal domains with no similarity to other nuclear receptors including Hr46 (Giguere, 1994).

Three isoforms of a novel member of the steroid hormone nuclear receptor superfamily related to theretinoic acid receptors have been identified. The three isoforms, referred to as ROR alpha 1, RORalpha 2, and ROR alpha 3, share common DNA- and putative ligand-binding domains but arecharacterized by distinct amino-terminal domains generated by alternative RNA processing. An exonencoding a functionally important subregion of the amino-terminal domain of the ROR alpha 2 isoformresides on the opposite strand of a cytochrome c-processed pseudogene. Binding site selection using invitro-synthesized proteins reveals that the ROR alpha 1 and ROR alpha 2 isoforms bind DNA asmonomers to hormone response elements composed of a 6-bp AT-rich sequence preceding a half-sitecore motif PuGGTCA (RORE). However, ROR alpha 1 and ROR alpha 2 display different bindingspecificities: ROR alpha 1 binds to and constitutively activates transcription from a large subset ofROREs, whereas ROR alpha 2 recognizes ROREs with strict specificity and displays weakertranscriptional activity. The differential DNA-binding activity of each isoform maps to their respectiveamino-terminal domains. Whereas truncation of the amino-terminal domain diminishes the ability ofROR alpha 1 to bind DNA, a similar deletion relaxes ROR alpha 2-binding specificity to that displayedby ROR alpha 1. Remarkably, transfer of the entire amino-terminal region of ROR alpha 1 oramino-terminal deletion of ROR alpha 2 confers RORE-binding specificities to heterologous receptors.These results demonstrate that the amino-terminal domain and the zinc finger region work in concert toconfer high affinity and specific DNA-binding properties to the ROR isoforms and suggest a novelstrategy to control DNA-binding activity of nuclear receptors (Giguere, 1994).

The expression of mouse orphan nuclear receptor ROR alpha was analyzed during postnatal development ofrodent brain. A peak of RORalpha expression is observed at postnatal 16 day (P16) in the Purkinje cells of cerebellum, neurons ofthe thalamus and the olfactory bulb. The hippocampus also expresses ROR alpha with anearlier peak at P7. Expression in cell types other than the Purkinje cells appeared transient. ROR alpha comprises at least four isoformsthat differ from one another in their N-terminal regions The different isoforms are under isoform-specific spatiotemporal expression regulation. The timing of itsexpression suggests that ROR alpha may be involved in regulation of postnatal maturation of specificclasses of neurons (Sashihara, 1996).

ROR alpha1 and RVR are orphan members of the superfamily of nuclear hormone receptors thatconstitutively activate and repress, respectively, gene transcription by binding to a common DNAsequence. A consensus binding site for ROR alpha1 and RVRis found in the first intron of the N-myc gene. This site is designated N-myc RORE (ROR response element).Unlike most of the intronic sequence, the region encompassing the N-myc RORE is highly conservedbetween human and mouse, underscoring its importance. ROR alpha1 andRVR specifically bind to the human and mouse N-myc ROREs and transactivate and transrepress,respectively, reporter constructs containing the ROREs. There is a direct modulation of an exogenously introduced N-myc gene by ROR alpha1 and RVRin COS-1 cells. This effect is mediated through the N-myc RORE, since mutation of this site abolishesthe regulatory effects of both receptors. While transfection of ROR alpha1 in P19 embryoniccarcinoma cells has no effect on the levels of endogenous N-myc mRNA, RVR down-regulates itsexpression. Mutation of the RORE increases the oncogenicpotential of the N-myc gene. Concomitant expression of ROR alpha1 and wild-type N-myc results in a twofold increasein the number of transformed foci. These observations show that ablation of the RORE results in a more oncogenic form ofN-myc and suggest that deregulation of the activity of the ROR alpha1 and RVR could contribute tothe initiation and progression of certain neoplasias (Dussault, 1997).

RAR alpha, ROR alpha and AP-1 activate the transcription of the murine laminin B1 gene promoter,which consists of three core elements. AP-1-activatedtranscription is further stimulated by RAR alpha, but not by ROR alpha. All of the three core elements are required fortransactivation by RAR alpha and ROR alpha, while any one of them is dispensable for AP-1-activatedtranscription. These results suggest that the modes of transactivation of the laminin B1 promoter aredifferent among the three transactivators (Matsui, 1996).

An everted repeat of the hexamer PuGGTCA located within thegamma F-crystallin promoter mediates activation of the murine gamma F-crystallin gene by retinoicacid and thyroid hormone receptors. ROR alpha is expressed in the murine lens and activates thegamma F-crystallin promoter. In contrast to the retinoic acid and thyroid hormone receptors, activationof the gamma F-crystallin promoter by ROR alpha requires binding to the single 3' half-site and spacersequences of gamma F-crystallin hormone response element (gamma F-HRE). ROR alpha-dependent activation is repressed by the competitive binding of retinoicacid receptor/retinoid X receptor heterodimers to the gamma F-HRE in the absence ofall-trans-retinoic acid. These studies suggest that the interplay of retinoid receptors and ROR alpha onthe gamma F-HRE may constitute an important mechanism regulating gamma F-crystallin geneexpression in the murine lens (Tini, 1995).

Rev-erb beta is a novel isoform of the Rev-erb alpha orphan nuclear receptor. TheDNA binding domains of Rev-erb alpha and beta are highly related to each other and to the retinoicacid related orphan receptor (ROR)/RZR subfamily of nuclear receptors. All threereceptors bind as monomers to the sequence AATGT-AGGTCA. Whereas ROR alpha 1 constitutivelyactivates transcription through this sequence, both isoforms of Rev-erb are inactive. Whencoexpressed, both Rev-erb isoforms suppress the transcriptional activity of ROR alpha 1. These datadefine Rev-erb and ROR/RZR as a family of related receptors with opposing activities on overlappingregulatory networks (Forman, 1994).

Homozygous staggerer (sg) mice show a characteristic severe cerebellar ataxia due to a cell-autonomous defect in the development of Purkinje cells. These cells show immature morphology, synaptic arrangement, biochemical properties and gene expression, and are reduced in numbers. In addition, sg heterozygotes show accelerated dendritic atrophy and cell loss, suggesting that sg has a role in mature Purkinje cells. Effects of this mutation on cerebellar development have been studied for 25 years, but its molecular basis has remained unknown. staggerer was genetically mapped to an interval of 160 kilobases on mouse chromosome 9 which was found to contain the gene encoding RORalpha, a member of the nuclear hormone-receptor superfamily. Staggerer mice were found to carry a deletion within the RORalpha gene that prevents translation of the ligand-binding homology domain. A model is proposed based on these results, in which RORalpha interacts with the thyroid hormone signalling pathway to induce Purkinje-cell maturation (Hamilton, 1996).

The ROR alpha is a member of the nuclear hormone receptor gene superfamily, and its deletion causes the staggerer mutation in mice. In the staggerer mutant mouse, Purkinje cells (PCs) are severely affected in cytology, synapse formation and gene expression. The presence of mediolateralcompartments unique to the staggerer cerebellum have been found, based on different degrees of abnormalities in their cytology and gene expression. Expression of the ROR alpha mRNA in developing mouse cerebellum has been studied, with a particular interest in its regional difference. At embryonic day 15, the ROR alpha mRNA is expressed at the highest level in the PC plate. The prominentexpression in PCs is maintained from late embryonic stage through mature stage.At any developmental stages, no apparent regional differences in the ROR alphamRNA expression are detected in the mediolateral and rostrocaudal axes of thecerebellum. The high expression from early developmental stages provides amolecular-anatomical basis for its important role in phenotypic differentiationof PCs. However, the even distribution in the cerebellum suggests that theunique staggerer compartments are not directly related to the loss of ROR alpha function (Nakagawa, 1997).

Retinoid-related orphan receptor alpha (RORalpha) is a member of the nuclear receptor superfamily. To study its physiological role, null-mutant mice were generated by targeted insertion of a lacZ reporter gene encoding the enzyme beta-galactosidase. In heterozygous RORalpha+/- mice, beta-galactosidase activity, indicative of RORalpha protein expression, was confined to the central nervous system, skin and testis. In the central nervous system, the RORalpha gene is expressed in cerebellar Purkinje cells, the thalamus, the suprachiasmatic nuclei, and retinal ganglion cells. In skin, RORalpha is strongly expressed in the hair follicle, the epidermis, and the sebaceous gland. Finally, the peritubular cells of the testis and the epithelial cells of the epididymis also strongly express RORalpha. Ataxic mouse mutant staggerer (sg/sg) has been found to be caused by a deletion in the RORalpha gene. The analysis of the cerebellar and the behavioral phenotype of homozygous RORalpha-/- mice proves identity to sg/sg mice. Although the absence of RORalpha causes dramatic developmental effects in the cerebellum, it has no apparent morphological effect on thalamus, hypothalamus, and retina. Similarly, testis and skin of RORalpha-/- mice display a normal phenotype. However, the pelage hair of both sg/sg and RORalpha-/- is significantly less dense and when shaved shows reluctance to regrow (Steinmayer, 1998).

Deficiency of thyroid hormone (TH) during the perinatal period results in severe neurological abnormalities in rodent cerebellar development. However, themolecular mechanisms of TH action in the developing cerebellum are not fullyunderstood. Of note, a mutant mouse, staggerer, in which the orphan nuclear hormone receptor ROR alpha gene is disrupted, exhibits cerebellar abnormalities similar to those seen in the hypothyroid animals, despite normal thyroid function. It was speculated that TH (tetraiodo-L-thyronine; T4) mayregulate ROR alpha gene expression, which then may regulate genes essential fornormal brain development. To test this hypothesis, the changes in RORalpha gene expression were studied in perinatal hypothyroid rat cerebellum and the effect of TH replacement was studied using Northern blot analysis, ribonuclease protection assay and in situ hybridization histochemistry. During cerebellar development, an approximately 3-fold increase in the cerebellar content of ROR alpha messenger RNA (mRNA) is seen in both propylthiouracil-treated, and propylthiouracil-treated and T4-replaced animals. However, the increase is accelerated when T4 is injected, although the ROR alpha mRNA content is identical, with or without T4, by 30 days after birth (P30). In contrast, T4treatment suppresses the TH receptor alpha1 and c-erbA alpha2 mRNA content byP30; retinoic acid X receptor-beta mRNA content is not influenced by thyroidstatus. A significant hybridization signal for ROR alpha mRNA is seen over Purkinje cells in the cerebellar cortex by in situ hybridization histochemistry.These results indicate that TH alters the timing of expression of the ROR alphagene in the Purkinje cells of the cerebellar cortex, which may, in turn,influence Purkinje cell differentiation (Koibuchi, 1998).

The cerebellum provides an excellent system for understanding how afferent and target neurons coordinate sequential intercellular signals and cell-autonomous genetic programs in development. Mutations in the orphan nuclear receptor RORalpha block Purkinje cell differentiation with a secondary loss of afferent granule cells. Early transcriptional targets of RORalpha include both mitogenic signals for afferent progenitors and signal transduction genes required to process their subsequent synaptic input. RORalpha acts through recruitment of gene-specific sets of transcriptional cofactors, including ß-catenin, p300, and Tip60, but appears independent of CBP. One target promoter is Sonic hedgehog, and recombinant Sonic hedgehog restores granule precursor proliferation in RORalpha-deficient cerebellum. These results suggest a link between RORalpha and ß-catenin pathways, confirm that a nuclear receptor employs distinct coactivator complexes at different target genes, and provide a logic for early RORalpha expression in coordinating expression of genes required for reciprocal signals in cerebellar development (Gold, 2003).

The retinoic acid-related orphan receptor alpha (RORalpha) is an orphan member of the subfamily 1 of nuclear hormone receptors. Recent structural and functional studies have led to the hypothesis that cholesterol or a cholesterol derivative is the natural ligand of RORalpha. The x-ray crystal structure of the ligand binding domain of RORalpha has been solved in complex with cholesterol-3-O-sulfate following a ligand exchange experiment. In contrast to the 3-hydroxyl of cholesterol, the 3-O-sulfate group makes additional direct hydrogen bonds with three residues of the RORalpha ligand binding domain, namely NH-Gln(289), NH-Tyr(290), and NH1-Arg(370). When compared with the complex with cholesterol, seven well ordered water molecules have been displaced, and the ligand is slightly shifted toward the hydrophilic part of the ligand binding pocket, which is ideally suited for interactions with a sulfate group. These additional ligand-protein interactions result in an increased affinity of cholesterol sulfate when compared with cholesterol, as shown by mass spectrometry analysis done under native conditions and differential scanning calorimetry. Moreover, mutational studies show that the higher binding affinity of cholesterol sulfate translates into an increased transcriptional activity of RORalpha. These findings suggest that cholesterol sulfate could play a crucial role in the regulation of RORalpha in vivo (Kallen, 2004).

The mammalian ROR/RZR subfamily of nuclear hormone receptors

ROR gamma, belongs to the ROR/RZR subfamily.The open reading frame of ROR gamma encodes a protein of 560 amino acid residues with a predictedmolecular mass of 63 kD. The amino acid sequence of ROR gamma exhibits a 50 and 51% identitywith those of ROR alpha/RZR alpha and RZR beta, respectively, whereas the DNA-binding domainsare 89% identical. ROR gamma is localized on human chromosome 1. ROR gamma is expressed in several tissues but is most highlyexpressed in skeletal muscle (Hirose, 1994).

The retinoid Z receptor beta (RZR beta), an orphan receptor, is a member of the retinoic acid receptor(RAR)/thyroid hormone receptor (TR) subfamily of nuclear receptors. RZR beta exhibits a highlyrestricted brain-specific expression pattern. So far, no natural RZR beta target gene has been identifiedand the physiological role of the receptor in transcriptional regulation remains to be elucidated.Electrophoretic mobility shift assays reveal binding of RZR beta to monomeric response elementscontaining the sequence AnnTAGGTCA, but RZR beta-mediated transactivation of reporter genes isonly achieved with two property spaced binding sites. RZR beta can functionas a cell-type-specific transactivator. In neuronal cells, GaI-RZR beta fusion proteins function aspotent transcriptional activators, whereas no transactivation can be observed in nonneuronal cells.Mutational analyses demonstrate that the activation domain (AF-2) of RZR beta and RAR alpha arefunctionally interchangeable. However, in contrast to RAR and TR, the RZR beta AF-2 cannotfunction autonomously as a transactivation domain. A novel repressorfunction exists for the C-terminal part of the putative ligand binding domain. It is proposed that thetranscriptional activity of RZR beta is regulated by an interplay of different receptor domains withcoactivators and corepressors (Greiner, 1996).

Most developing thymocytes undergo apoptosis because they cannot interactproductively with molecules encoded by the major histocompatibility complex.Mice lacking the orphan nuclear hormone receptor RORgammalose thymic expression of the anti-apoptotic factor Bcl-xL. RORgamma thusregulates the survival of CD4+8+ thymocytes and may control the temporal windowduring which thymocytes can undergo positive selection. RORgamma is alsorequired for development of lymph nodes and Peyer's patches, but not splenicfollicles. In its absence, there is a loss of a population of CD3-CD4+CD45+ cellsthat normally express RORgamma and that are likely early progenitors of lymphoidorgans. Hence, RORgamma has critical functions in T cell repertoire selectionand lymphoid organogenesis (Sun, 2000).

Transcriptional regulation of RORalpha

Hypoxia plays a key role in the pathophysiology of many disease states, and expression of the retinoic acid receptor-related orphan receptor alpha (RORalpha) gene increases under hypoxia. The mechanism for this transient hypoxia-induced increase in RORalpha expression was investigated. Reverse transcription-coupled PCR analysis revealed that the steady-state level of mRNA for the RORalpha4 isoform, but not the RORalpha1 isoform, increases in HepG2 cells after 3 h of hypoxia. Transient transfection studies showed that the hypoxia-induced increase in RORalpha4 mRNA occurs at the transcriptional level and is dependent on a hypoxia-responsive element (HRE) located downstream of the promoter. A dominant-negative mutant of hypoxia-inducible factor-1alpha (HIF-1alpha) abrogates the transcription activated by hypoxia as well as the transcription activated by exogenously expressed HIF-1alpha, demonstrating the direct involvement of HIF-1alpha in the transcriptional activation. However, HIF-1 alone is not sufficient to activate transcription in hypoxic conditions but, rather, required Sp1/Sp3, which binds to a cluster of GC-rich sequences adjacent to the HRE. Deletion of one or more of these GC boxes reduced or eliminated the HIF-1-dependent transcription. Together, these results suggest that the hypoxia-responsive region of the RORalpha4 promoter is composed of the HRE and GC-rich sequences and that the transcriptional activation under hypoxia is conferred through the cooperation of HIF-1 with Sp1/Sp3 (Miki, 2004).

ROR alpha augments thyroid hormone receptor-mediated transcriptional activation

The role of an orphan nuclear hormone receptor, ROR alpha, on thyroid hormone (TH) receptor (TR)-mediated transcription on a TH-response element (TRE) was investigated. A transient transfection study using various TREs [i.e., F2 (chick lysozyme TRE), DR4 (direct repeat), andpalindrome TRE] and TR and ROR alpha1 was performed. When ROR alpha1 and TR werecotransfected into CV1 cells, ROR alpha1 enhanced the transactivation byliganded-TR on all TREs tested without an effect on basal repression byunliganded TR. However, by electrophoretic mobility shift assay, although ROR alpha bound to all TREs tested as a monomer, no (or weak) TR andROR alpha1 heterodimer formation was observed on various TREs except when aputative ROR-response element was present. The transactivation by ROR alpha1 ona ROR-response element, which does not contain a TRE, was not enhanced by TR.The effect of ROR alpha1 on the TREs is unique, because, whereas other nuclearhormone receptors (such as vitamin D receptor) may competitively bind to TRE toexert dominant negative function, ROR alpha1 augments TR action. These resultsindicate that ROR alpha1 may modify the effect of liganded TR on TH-responsivegenes. Because TR and ROR alpha are coexpressed in cerebellar Purkinje cells,and perinatal hypothyroid animals and ROR alpha-disrupted animals show similarabnormalities of this cell type, cross-talk between these two receptors may playa critical role in Purkinje cell differentiation (Koibuchi, 1999).

A potential role for ROR subfamily members as melatonin binding proteins

The two subtypes of retinoid Z receptor (RZR alpha and beta) and the three splicing variants ofretinoid orphan receptor (ROR alpha 1, alpha 2, and alpha 3) form a subfamily within the superfamilyof nuclear hormone receptors. The pineal gland hormone melatonin is anatural ligand of RZR alpha and RZR beta. Ligand-induced transcriptional control is thereforeproposed to mediate physiological functions of melatonin in the brain where RZR beta is expressed, andalso in peripheral tissues, where RZR alpha is found. A response element in the promoter of 5-lipoxygenasebinds specifically RZR alpha and ROR alpha 1, but not ROR alpha 2 and alpha 3. 5-Lipoxygenase is akey enzyme in the biosynthesis of leukotrienes, which are known to be allergic and inflammatorymediators. The activity of the whole 5-lipoxygenase promoter as well as of theRZR response element fused to the heterologous thymidine kinase promoter can be repressed bymelatonin. The hormone down-regulates the expression of 5-lipoxygenase about 5-fold in Blymphocytes, which express RZR alpha. In contrast, 5-lipoxygenase mRNA levels are not affected indifferentiated monocytic and granulocytic cell lines, which do not express RZR alpha. This indicatesthat 5-lipoxygenase is the first natural RZR alpha responding gene. These results open up anew perspective in understanding the involvement of melatonin in inflammatory and immunologicalreactions (Steinhilber, 1995).

The orphan receptors RZR alpha, RZR beta, ROR alpha 1, RZR alpha 2, ROR alpha 3, and RORgamma form a subfamily within the superfamily of nuclear hormone receptors. Experimentalevidence suggests the pineal gland hormone melatonin is the natural ligand for these nuclear receptors. This discovery is rather surprising, since it is commonly thought that melatoninacts exclusively through membrane receptors. However, these new findings establish a nuclearsignaling pathway for melatonin, i.e., direct ligand-induced control of target gene transcription, whichmost probably mediates part of the physiological functions of the hormone. Interestingly, the veryrecently identified first RZR/melatonin responding gene, 5-lipoxygenase, is not expressed in the brainand is not involved in circadian rhythmicity, but rather acts in the periphery, mainly in myeloid cells, asone of the key enzymes of allergic and inflammatory reactions. Thus, nuclear melatonin signalingopens up a new perspective in understanding the actions of the pineal gland hormone (Carlberg, 1995).

RORalpha regulates circadian transcription

Mammalian circadian rhythms are generated by a feedback loop in which BMAL1 and CLOCK, players of the positive limb, activate transcription of the cryptochrome and period genes, components of the negative limb. Bmal1 and Per transcription cycles display nearly opposite phases and are thus governed by different mechanisms. The orphan nuclear receptor REV-ERBalpha has been identified as the major regulator of cyclic Bmal1 transcription. Circadian Rev-erbalpha expression is controlled by components of the general feedback loop. Thus, REV-ERBalpha constitutes a molecular link through which components of the negative limb drive antiphasic expression of components of the positive limb. While REV-ERBalpha influences the period length and affects the phase-shifting properties of the clock, it is not required for circadian rhythm generation (Preitner, 2002).

The mammalian circadian clock plays an integral role in timing rhythmic physiology and behavior, such as locomotor activity, with anticipated daily environmental changes. The master oscillator resides within the suprachiasmatic nucleus (SCN), which can maintain circadian rhythms in the absence of synchronizing light input. A genomics-based approach is described to identify circadian activators of Bmal1, itself a key transcriptional activator that is necessary for core oscillator function. Using cell-based functional assays, as well as behavioral and molecular analyses, Rora has been identified as an activator of Bmal1 transcription within the SCN. Roraalpha is required for normal Bmal1 expression and consolidation of daily locomotor activity and is regulated by the core clock in the SCN. These results suggest that opposing activities of the orphan nuclear receptors Rora and Rev-erb alpha, which represses Bmal1 expression, are important in the maintenance of circadian clock function (Sato, 2004).

The PAS (PER-ARNT-SIM) helix-loop-helix transcription factor BMAL1 (also known as MOP3) is an essential component of the circadian pacemaker in mammals. The retinoic acid receptor-related orphan receptor RORalpha (NR1F1) directly activates transcription of Bmal1 through two conserved RORalpha response elements that are required for cell-autonomous transcriptional oscillation of Bmal1 mRNA. Positive involvement of RORalpha in generation of the Bmal1 circadian oscillation was verified by behavioral analyses of RORalpha-deficient staggerer mice that showed aberrant locomotor activity and unstable rhythmicity. In cultured cells, loss of endogenous RORalpha protein resulted in a dampened circadian rhythm of Bmal1 transcription, further indicating that RORalpha is a functional component of the cell-autonomous core circadian clock. These results indicate that RORalpha acts to promote Bmal1 transcription, thereby maintaining a robust circadian rhythm (Akashi, 2005).

Circadian rhythms are generated by an extremely complicated transcription-translation feedback loop. To precisely analyze the molecular mechanisms of the circadian clock, it is critical to monitor multiple gene expressions and/or interactions with their transcription factors simultaneously. A novel reporter assay system, the tricolor reporter in vitro assay system, has been developed that consists of green- and red-emitting Phrixothrix luciferases as dual reporters and blue-emitting Renilla luciferase as internal control. This system has been successfully employed in analyzing the effects of clock gene products on the enhancer elements of Per1 and Bmal1 promoters. The results indicate that the orphan nuclear receptor RORalpha regulates bidirectionally Bmal1 (positively) and Per1 (negatively) transcriptions simultaneously (Nakajima, 2004).

RORalpha regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR

The staggerer mice carry a deletion in the RORalpha gene and have a prolonged humoral response, overproduce inflammatory cytokines, and are immunodeficient. Furthermore, the staggerer mice display lowered plasma apoA-I/-II, decreased plasma high density lipoprotein cholesterol and triglycerides, and develop hypo-alpha-lipoproteinemia and atherosclerosis. However, relatively little is known about RORalpha in the context of target tissues, target genes, and lipid homeostasis. For example, RORalpha is abundantly expressed in skeletal muscle, a major mass peripheral tissue that accounts for approximately 40% of total body weight and 50% of energy expenditure. This lean tissue is a primary site of glucose disposal and fatty acid oxidation. Consequently, muscle has a significant role in insulin sensitivity, obesity, and the blood-lipid profile. In particular, the role of RORalpha in skeletal muscle metabolism has not been investigated, and the contribution of skeletal muscle to the ROR-/- phenotype has not been resolved. Ectopic dominant negative RORalpha expression in skeletal muscle cells has been used to understand the regulatory role of RORs in this major mass peripheral tissue. Exogenous dominant negative RORalpha expression in skeletal muscle cells represses the endogenous levels of RORalpha and -gamma mRNAs and ROR-dependent gene expression. Moreover, attenuated expression is observed of many genes involved in lipid homeostasis. Furthermore, the muscle carnitine palmitoyltransferase-1 and caveolin-3 promoters are directly regulated by ROR and coactivated by p300 and PGC-1. This study implicates RORs in the control of lipid homeostasis in skeletal muscle. In conclusion, it is speculated that ROR agonists would increase fatty acid catabolism in muscle and suggested that selective activators of ROR may have therapeutic utility in the treatment of obesity and atherosclerosis (Lau, 2005).

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Hormone receptor-like in 46: Biological Overview | Regulation | Developmental Biology | Effects of Mutation | References

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