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Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells.

ABSTRACT: Retinoic acid-related Orphan Receptor alpha (ROR?; NR1F1) is a widely distributed nuclear receptor involved in several (patho)physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rhythm. To better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by ROR? in liver cells by generating HepG2 human hepatoma cells stably over-expressing ROR?. Genes whose expression was altered in these cells versus control cells were displayed using micro-arrays followed by qRT-PCR analysis. Expression of these genes was also altered in cells in which ROR? was transiently over-expressed after adenoviral infection. A number of the genes found were involved in known pathways controlled by ROR?, for instance LPA, NR1D2 and ADIPOQ in lipid metabolism, ADIPOQ and PLG in inflammation, PLG in fibrinolysis and NR1D2 and NR1D1 in circadian rhythm. This study also revealed that genes such as G6PC, involved in glucose homeostasis, and AGRP, involved in the control of body weight, are also controlled by ROR?. Lastly, SPARC, involved in cell growth and adhesion, and associated with liver carcinogenesis, was up-regulated by ROR?. SPARC was found to be a new putative ROR? target gene since it possesses, in its promoter, a functional RORE as evidenced by EMSAs and transfection experiments. Most of the other genes that we found regulated by ROR? also contained putative ROREs in their regulatory regions. Chromatin immunoprecipitation (ChIP) confirmed that the ROREs present in the SPARC, PLG, G6PC, NR1D2 and AGRP genes were occupied by ROR? in HepG2 cells. Therefore these genes must now be considered as direct ROR? targets. Our results open new routes on the roles of ROR? in glucose metabolism and carcinogenesis within cells of hepatic origin.

SUBMITTER: Chauvet C

PROVIDER: S-EPMC3144224 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells.

Chauvet Caroline C Vanhoutteghem Amandine A Duhem Christian C Saint-Auret Gaëlle G Bois-Joyeux Brigitte B Djian Philippe P Staels Bart B Danan Jean-Louis JL

PloS one 20110726 7

Retinoic acid-related Orphan Receptor alpha (RORα; NR1F1) is a widely distributed nuclear receptor involved in several (patho)physiological functions including lipid metabolism, inflammation, angiogenesis, and circadian rhythm. To better understand the role of this nuclear receptor in liver, we aimed at displaying genes controlled by RORα in liver cells by generating HepG2 human hepatoma cells stably over-expressing RORα. Genes whose expression was altered in these cells versus control cells wer ...[more]

PMID: 21818335

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Project description:ObjectivesThe retinoic acid receptor (RAR)-related orphan receptor α gene (RORA) is implicated as a candidate for age-related macular degeneration (AMD) through a previous microarray expression study, linkage data, biological plausibility, and 2 clinic-based cross-sectional studies. We aimed to determine if common variants in RORA predict future risk of neovascular AMD.MethodsWe measured genotypes for 18 variants in intron 1 of the RORA gene among 164 cases who developed neovascular AMD and 485 age- and sex-matched controls in a prospective, nested, case-control study within the Nurses' Health Study and the Health Professionals Follow-up Study. We determined the incidence rate ratios and 95% confidence intervals (CI) for neovascular AMD for each variant and examined interactions with other AMD-associated variants and modifiable risk factors.ResultsWe identified one single-nucleotide polymorphism (rs12900948) that was significantly associated with increased incidence of neovascular AMD. Participants with 1 and 2 copies of the G allele were 1.73 (CI, 1.32-2.27) and 2.99 (CI, 1.74-5.14) times more likely to develop neovascular AMD. Individuals homozygous for both the G allele of rs12900948 and ARMS2 A69S had a 40.8-fold increased risk of neovascular AMD (CI, 10.1-164; P = .017). Cigarette smokers who carried 2 copies of the G allele had a 9.89-fold risk of neovascular AMD but the interaction was not significant (P = .08). We identified a significant AMD-associated haplotype block containing the single-nucleotide polymorphisms rs730754, rs8034864, and rs12900948, with P values for ACA = 1.16 × 10(-9), ACG = 5.85 × 10(-12), and GAA = .0001 when compared with all other haplotypes.ConclusionsCommon variants and haplotypes within the RORA gene appear to act synergistically with the ARMS2 A69S polymorphism to increase risk of neovascular AMD. These data add further evidence of a high level of complexity linking genetic and modifiable risk factors to AMD development and should help efforts at risk prediction.

Dataset Information

Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells.

Publications

Control of gene expression by the retinoic acid-related orphan receptor alpha in HepG2 human hepatoma cells.

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