Identification of the human ApoAV gene as a novel RORα target gene

Lind, Ulrika; Nilsson, Thomas; McPheat, Jane; Strömstedt, Per-Erik; Bamberg, Krister; Balendran, Clare A.; Kang, Daiwu

doi:10.1016/j.bbrc.2005.02.151

Cited by 28 publications

(21 citation statements)

References 51 publications

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“…through binding to the half-core AGGTCA DR1/PPRE site [45], whereas mouse apoa5 is not, due to a nucleotide difference in the half-core site which prevents RORα binding to the mouse promoter [32]. Consistently, mouse Apoa5 gene expression is not affected in the staggerer mutant mouse which carries a deletion in the gene encoding for RORα [32].…”

Section: Accepted M Manuscriptsupporting

confidence: 59%

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha

Prieur

Lesnik

Moreau

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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Section: Accepted M Manuscriptsupporting

confidence: 59%

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha

Prieur

Lesnik

Moreau

et al. 2009

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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“…2B). ApoA-V/RORE is a prototypic RORE derived from the ApoA-V gene promoter (Lind et al, 2005). It is noteworthy that ROR␥ could also bind to Cyp7b1/RORE, but the binding was substantially weaker compared with that of ROR␣ (Fig.…”

Section: Resultsmentioning

confidence: 97%

Identification of Oxysterol 7α-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor α (RORα) (NR1F1) Target Gene and a Functional Cross-Talk between RORα and Liver X Receptor (NR1H3)

Wada¹,

Kang²,

Angers³

et al. 2007

Mol Pharmacol

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The retinoid-related orphan receptors (RORs) and liver X receptors (LXRs) were postulated to have distinct functions. RORs play a role in tissue development and circadian rhythm, whereas LXRs are sterol sensors that affect lipid homeostasis. In this study, we revealed a novel function of ROR␣ (NR1F1) in regulating the oxysterol 7␣-hydroxylase (Cyp7b1), an enzyme critical for the homeostasis of cholesterol, bile acids, and oxysterols. The expression of Cyp7b1 gene was suppressed in the ROR␣ null (ROR␣ sg/sg ) mice, suggesting ROR␣ as a positive regulator of Cyp7b1. Promoter analysis established Cyp7b1 as a transcriptional target of ROR␣, and transfection of ROR␣ induced the expression of endogenous Cyp7b1 in the liver. Interestingly, Cyp7b1 regulation seemed to be ROR␣-specific, because ROR␥ had little effect. Reporter gene analysis showed that the activation of Cyp7b1 gene promoter by ROR␣ was suppressed by LXR␣ (NR1H3), whereas ROR␣ inhibited both the constitutive and ligand-dependent activities of LXR␣. The mutual suppression between ROR␣ and LXR was supported by the in vivo observation that loss of ROR␣ increased the expression of selected LXR target genes, leading to hepatic triglyceride accumulation. Likewise, mice deficient of LXR ␣ and ␤ isoforms showed activation of selected ROR␣ target genes. Our results have revealed a novel role for ROR␣ and a functional interplay between ROR␣ and LXR in regulating endo-and xenobiotic genes, which may have broad implications in metabolic homeostasis.

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“…Staels (1,5) and our group (3,8) amongst others have previously demonstrated that the α1 isoform has a physiological role in the regulation of lipid homeostasis. To further characterize the line of mice, we examined expression of a bona fide RORα (1 and 4) target gene, apolipoprotein A5, characterized by two independent groups (24,25), which was very significantly decreased in the Tg-RORα1ΔDE mice (Figure 1G). These data demonstrate the line of Tg-RORα1ΔDE mice, express the ectopic transcript, suppress endogenous RORα1 mRNA expression and attenuate RORα1-dependent gene expression.…”

Section: Resultsmentioning

confidence: 99%

Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle

Raichur

Fitzsimmons

Myers

et al. 2010

Nucleic Acids Research

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The retinoic acid receptor-related orphan receptor (ROR) alpha has been demonstrated to regulate lipid metabolism. We were interested in the RORα1 dependent physiological functions in skeletal muscle. This major mass organ accounts for ∼40% of the total body mass and significant levels of lipid catabolism, glucose disposal and energy expenditure. We utilized the strategy of targeted muscle-specific expression of a truncated (dominant negative) RORα1ΔDE in transgenic mice to investigate RORα1 signaling in this tissue. Expression profiling and pathway analysis indicated that RORα influenced genes involved in: (i) lipid and carbohydrate metabolism, cardiovascular and metabolic disease; (ii) LXR nuclear receptor signaling and (iii) Akt and AMPK signaling. This analysis was validated by quantitative PCR analysis using TaqMan low-density arrays, coupled to statistical analysis (with Empirical Bayes and Benjamini–Hochberg). Moreover, westerns and metabolic profiling were utilized to validate the genes, proteins and pathways (lipogenic, Akt, AMPK and fatty acid oxidation) involved in the regulation of metabolism by RORα1. The identified genes and pathways were in concordance with the demonstration of hyperglycemia, glucose intolerance, attenuated insulin-stimulated phosphorylation of Akt and impaired glucose uptake in the transgenic heterozygous Tg-RORα1ΔDE animals. In conclusion, we propose that RORα1 is involved in regulating the Akt2-AMPK signaling pathways in the context of lipid homeostasis in skeletal muscle.

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Identification of the human ApoAV gene as a novel RORα target gene

Cited by 28 publications

References 51 publications

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha

Differential regulation of the human versus the mouse apolipoprotein AV gene by PPARalpha

Identification of Oxysterol 7α-Hydroxylase (Cyp7b1) as a Novel Retinoid-Related Orphan Receptor α (RORα) (NR1F1) Target Gene and a Functional Cross-Talk between RORα and Liver X Receptor (NR1H3)

Identification and validation of the pathways and functions regulated by the orphan nuclear receptor, ROR alpha1, in skeletal muscle

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