OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor.

Teboul, Michèle; Enmark, Eva; Li, Qiao; Wikström, Ann Charlotte; Pelto‐Huikko, Markku; Gustafsson, Jan‐Åke

doi:10.1073/pnas.92.6.2096

Cited by 220 publications

(144 citation statements)

References 35 publications

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“…LXR␣ and the closely related orphan receptor LXR␤ are broadly expressed and bind to DNA as heterodimers with the retinoid X receptors (RXRs) (11)(12)(13)(14). As part of an effort to identify natural LXR ligands, we have found that the oxysterols 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol activate both LXR␣ and LXR␤ at concentrations consistent with those found in tissue extracts.…”

mentioning

confidence: 83%

“…We note that both LXRs are expressed in the liver. Interestingly, Northern analyses have demonstrated that LXR␤ is expressed in the brain (14). More detailed in situ studies have shown that LXR␤ is broadly expressed in fetal brain and that its expression becomes more restricted in postnatal and adult brains (26).…”

Section: Oxysterols Activate the Lxr Nuclear Receptors 3139mentioning

confidence: 99%

“…This putative response element is composed of a nearly perfect tandem repeat of the nuclear receptor half-site recognition sequence AG(G/T)TCA separated by four nucleotides, a so-called DR-4 motif (17). This type of DR-4 response element has been shown to function as a high affinity binding site for heterodimers between RXR and the orphan nuclear receptors LXR␣ and LXR␤ (11)(12)(13)(14).…”

Section: The Cyp7a Promotor Contains An Lxr-rxr Heterodimermentioning

confidence: 99%

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Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

Lehmann¹,

Kliewer²,

Moore³

et al. 1997

Journal of Biological Chemistry

1,119

847

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Accumulation of cholesterol causes both repression of genes controlling cholesterol biosynthesis and cellular uptake and induction of cholesterol 7␣-hydroxylase, which leads to the removal of cholesterol by increased metabolism to bile acids. Here, we report that LXR␣ and LXR␤, two orphan members of the nuclear receptor superfamily, are activated by 24(S),25-epoxycholesterol and 24(S)-hydroxycholesterol at physiologic concentrations. In addition, we have identified an LXR response element in the promoter region of the rat cholesterol 7␣-hydroxylase gene. Our data provide evidence for a new hormonal signaling pathway that activates transcription in response to oxysterols and suggest that LXRs play a critical role in the regulation of cholesterol homeostasis.Cholesterol (CH) 1 is a major structural constituent of cellular membranes and serves as the biosynthetic precursor for bile acids and steroid hormones. Animal cells can obtain CH endogenously through de novo synthesis from acetyl-CoA or exogenously through receptor-mediated endocytosis of low density lipoproteins. Cells must balance the internal and external sources of CH so as to maintain mevalonate biosynthesis while at the same time avoiding the accumulation of excess CH, which can result in diseases such as atherosclerosis, gallstones, and several lipid storage disorders (1).CH homeostasis is maintained in part through feedback regulation of the low density lipoprotein receptor gene and at least two genes encoding enzymes in the CH biosynthetic pathway, 3-hydroxy-3-methylglutaryl coenzyme A synthase and 3-hydroxy-3-methylglutaryl coenzyme A reductase (1). Although increases in dietary CH lead to the inhibition of expression of these genes in vivo, it remains unclear whether CH or CH metabolites are responsible for this inhibition (2). Experiments performed in vitro using several different cell lines have indicated that derivatives of CH that are oxygenated on the CH side chain are significantly more potent in the suppression of sterol biosynthesis than CH (3). These oxysterols are produced through the actions of P450 enzymes in various metabolic pathways including bile acid synthesis in the liver and sex hormone synthesis in the adrenal glands. The in vitro activities of oxysterols together with their presence in vivo suggests that oxysterols may serve in metabolic feedback loops to regulate CH homeostasis.Although CH and its oxysterol metabolites can repress gene transcription, in at least one instance dietary CH has been shown to stimulate gene expression. Expression of the cholesterol 7␣-hydroxylase (CYP7A) gene, which encodes the enzyme responsible for the initial and rate-limiting step in the conversion of CH to bile acids (4), is up-regulated in rats fed a CH-rich diet (5-7). This stimulatory effect provides a regulatory mechanism whereby excess dietary CH can be converted to more polar bile acids for subsequent removal from the body. Although the molecular mechanism is unknown, induction of CYP7A expression in the presence of CH occurs at the level...

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mentioning

confidence: 83%

Section: Oxysterols Activate the Lxr Nuclear Receptors 3139mentioning

confidence: 99%

Section: The Cyp7a Promotor Contains An Lxr-rxr Heterodimermentioning

confidence: 99%

See 1 more Smart Citation

Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

Lehmann¹,

Kliewer²,

Moore³

et al. 1997

Journal of Biological Chemistry

1,119

847

View full text Add to dashboard Cite

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“…LXR␣ and LXR␤ are members of the nuclear receptor supergene family of ligand-activated transcription factors (22,23). Their endogenous ligands are oxysterols (24,25).…”

mentioning

confidence: 99%

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Kim¹,

Fan²,

Gabbi³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

129

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Administration of ␤-sitosterol (42 mg/kg per day) for 3 weeks to 8-month-old male LXR␤ ؊/؊ mice resulted in the death of motor neurons in the lumbar region of the spinal cord and loss of tyrosine hydroxylase-positive dopaminergic neurons in the substantia nigra. In mice at 5 months of age, ␤-sitosterol had no observed toxicity but at 16 months of age, it caused severe paralysis and symptoms typical of dopaminergic dysfunction in LXR␤ ؊/؊ mice. WT mice were not affected by these doses of ␤-sitosterol. In 5-month-old mice, levels of the intestinal transporters, ABCG5/8 and Niemann-Pick C1 Like 1, were not affected by loss of liver X receptor (LXR) ␤ and/or treatment with ␤-sitosterol nor were there changes in plasma levels of cholesterol or ␤-sitosterol. In 8-monthold LXR␤ ؊/؊ mice there was activation of microglia in the substantia nigra pars reticulata and aggregates of ubiquitin and TDP-43 in the cytoplasm of large motor neurons in the lumbar spinal cord. Brain cholesterol concentrations were higher in LXR␤ ؊/؊ than in their WT counterparts, and treatment with ␤-sitosterol reduced brain cholesterol in both WT and LXR␤ ؊/؊ mice. In LXR␤ ؊/؊ mice but not in WT mice levels of 24-hydrocholesterol were increased upon ␤-sitosterol treatment. These data indicate that multiple mechanisms are involved in the sensitivity of LXR␤ ؊/؊ mice to ␤-sitosterol. These include activation of microglia, accumulation of protein aggregates in the cytoplasm of large motor neurons, and depletion of brain cholesterol.central nervous system ͉ cholesterol ͉ microglia ͉ neurodegenerative disease ͉ nuclear receptor

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“…Finally, RXRs may also be the heterodimeric partners of a number of orphan nuclear receptors, including members of the FXR/RLD-1/LXR/UR family (Apfel et al 1994;Song et al 1994;Forman et al 1995a;Seol et al 1995;Teboul et al 1995;Willy et al 1995; note that UR has also been named OR-1 or RIP15), members of the NGFI-B/ NURR-1 family (Forman et al 1995b;Perlmann and Jansson 1995), and the orphan receptor MB67 (Baes et al 1994).…”

mentioning

confidence: 99%

Abnormal spermatogenesis in RXR beta mutant mice.

Kastner¹,

Mark²,

Leid³

et al. 1996

Genes Dev.

306

214

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We have generated mouse lines in which the RXRI3 gene was disrupted by homologous recombination. Approximately 50% of the RXR~ homozygous mutants died before or at birth, but those that survived appeared normal except that the males were sterile, owing to oligo-astheno-teratozoospermia. Failure of spermatid release occurred within the germinal epithelium, and the epididymis contained very few spermatozoa that, in addition, exhibited abnormal acrosomes and tails. There was a progressive accumulation of lipids within the mutant Sertoli cells, which were histochemically characterized as unsaturated triglycerides. In old mutant males, progressive degeneration of the germinal epithelium occurred, ending with the formation of acellular lipid-filled tubules. The selective expression of RXR[~ in Sertoli cells, together with the timing of appearence of the histological abnormalities, suggests that the primary defect resulting from the mutation resides in these cells.

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OR-1, a member of the nuclear receptor superfamily that interacts with the 9-cis-retinoic acid receptor.

Cited by 220 publications

References 35 publications

Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

Activation of the Nuclear Receptor LXR by Oxysterols Defines a New Hormone Response Pathway

Liver X receptor β (LXRβ): A link between β-sitosterol and amyotrophic lateral sclerosis–Parkinson's dementia

Abnormal spermatogenesis in RXR beta mutant mice.

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