Mitogenic effect of retinoid X receptor agonists in rat liver

Standeven, Andrew M.; Escobar, Maria; Beard, Richard L.; Yuan, Yang-Dar; Chandraratna, Roshantha A.S.

doi:10.1016/s0006-2952(97)00209-8

Cited by 25 publications

(23 citation statements)

References 28 publications

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“…T1317, AGN, and D3T exposure led to altered regulation of a subset of these genes consistent with less pronounced effects of T1317 and AGN on fatty acid catabolism compared with PPAR␣ agonists (25,37).…”

Section: Regulation Of Lipid Homeostasis Genes By Cr-crmentioning

confidence: 76%

Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors

Corton

Apte

Anderson

et al. 2004

Journal of Biological Chemistry

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109

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The obesity epidemic in industrialized countries is associated with increases in cardiovascular disease (CVD) and certain types of cancer. In animal models, caloric restriction (CR) suppresses these diseases as well as chemical-induced tissue damage. These beneficial effects of CR overlap with those altered by agonists of nuclear receptors (NR) under control of the fastingresponsive transcriptional co-activator, peroxisome proliferator-activated co-activator 1␣ (PGC-1␣). In a screen for compounds that mimic CR effects in the liver, we found statistically significant overlaps between the CR transcript profile in wild-type mice and the profiles altered by agonists of lipid-activated NR, including peroxisome proliferator-activated receptor ␣ (PPAR␣), liver X receptor, and their obligate heterodimer partner, retinoid X receptor. The overlapping genes included those involved in CVD (lipid metabolism and inflammation) and cancer (cell fate). Based on this overlap, we hypothesized that some effects of CR are mediated by PPAR␣. As determined by transcript profiling, 19% of all gene expression changes in wild-type mice were dependent on PPAR␣, including Cyp4a10 and Cyp4a14, involved in fatty acid -oxidation, acute phase response genes, and epidermal growth factor receptor but not increases in PGC-1␣. CR protected the livers of wild-type mice from damage induced by thioacetamide, a liver toxicant and hepatocarcinogen. CR protection was lost in PPAR␣-null mice due to inadequate tissue repair. These results demonstrate that PPAR␣ mediates some of the effects of CR and indicate that a pharmacological approach to mimicking many of the beneficial effects of CR may be possible.

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Section: Regulation Of Lipid Homeostasis Genes By Cr-crmentioning

confidence: 76%

Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors

Corton

Apte

Anderson

et al. 2004

Journal of Biological Chemistry

Self Cite

109

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“…WY-treated mice harboring a liver-specific deletion of the RXR␣ gene showed greatly reduced hepatic induction of Acox1, Cyp4a1, and Fabp1 (Wan et al, 2000). RXR agonists increased the expression of genes under control of PPAR␣, including Fabp1 (Poirier et al, 1997), bifunctional enzyme (also known as MFP-I), and Acox1 (Standeven et al, 1997;Mukherjee et al, 1998), and fatty acid transfer protein and acyl-CoA synthetase (Martin et al, 2000). The RXR agonist LGD1069 increased the expression of Cyp4a, thiolase, Acox1 as well as cholesterol levels in wild-type but not PPAR␣-null mice (Ouamrane et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Both PPAR␣ and RXR agonists increase cell proliferation in rat liver (Standeven et al, 1997;Corton et al, 2000). The ability of RXR agonists to increase cell proliferation in mouse liver and dependence on PPAR␣ is not known.…”

Section: Ppar␣ Rxr and Lxr Regulate Overlapping Genes 1443mentioning

confidence: 99%

Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor α, Retinoid X Receptor, and Liver X Receptor in Mouse Liver

Anderson

Dunn²,

Laughter³

et al. 2004

Mol Pharmacol

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Lipid homeostasis is controlled in part by the nuclear receptors peroxisome proliferator (PP)-activated receptor ␣ (PPAR␣) and liver X receptor (LXR) through regulation of genes involved in fatty acid and cholesterol metabolism. Exposure to agonists of retinoid X receptor (RXR), the obligate heterodimer partner of PPAR␣, and LXR results in responses that partially overlap with those of PP. To better understand the gene networks regulated by these nuclear receptors, transcript profiles were generated from the livers of wild-type and PPAR␣-null mice exposed to the RXR pan-agonist 3,7-dimethyl-6S,7S-methano, 7-[1,1,4,4-tetramethyl-1,2,3,4-tetrahydronaphth-7-yl]-2E,4E-heptadienoic acid (AGN194,204) or the PPAR pan-agonist WY-14,643 (WY; pirinixic acid) and compared with the profiles from the livers of wild-type and LXR␣/LXR␤-null mice after exposure to the LXR agonist N- (2,2,2-trifluoroethyl)-N-[4-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethylethyl)phenyl] sulfonamide (T0901317). All 218 WY-regulated genes altered in wild-type mice required PPAR␣. Remarkably, ϳ80% of genes regulated by AGN194,204 required PPAR␣ including cell-cycle genes, consistent with AGN-induced hepatocyte proliferation having both PPAR␣-dependent and -independent components. Overlaps of ϳ31 to 62% in the transcript profiles of WY, AGN194,204, and T0901317 required PPAR␣ and LXR␣/LXR␤ for statistical significance. Ofthe 50 overlapping genes regulated by T0901317 and WY, all but one were regulated in a similar direction. These results 1) identify new transcriptional targets of PPAR␣ and RXR important in regulating lipid metabolism and liver homeostasis, 2) illustrate the importance of PPAR␣ in regulation of gene expression by a prototypical PP and by an RXR agonist, and 3) provide support for an axis of PPAR␣-RXR-LXR in which agonists for each nuclear receptor regulate an overlapping set of genes in the mouse liver.

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“…All-trans RA and its isomer 9-cis RA bind the RARs with high affinity (K D ~ 1 nM), whereas the RXRs bind only 9-cis RA partner is occupied [20,25]. RXR-specific ligands have significant in vivo activity unrelated to the RARs, including lowering of serum glucose and triglycerides in diabetic animals and induction of some enzymes of lipid oxidation [8,26,27]. The metabolic effects of RXR ligands probably occur through one or more non-RAR/RXR heterodimers.…”

Section: Introductionmentioning

confidence: 99%

Therapeutic Applications for Ligands of Retinoid Receptors

Thacher

Vasudevan²,

Chandraratna³

2000

CPD

116

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Synthetic retinoids, ligands for the RAR and RXR members of the steroid/thyroid superfamily of nuclear hormone receptors, are used for the treatment of psoriasis, acne, photoaging and cancer. Retinoid mechanisms of action for these conditions largely involve effects on epithelial differentiation and modulation of inflammation with some impact on the immune system. Retinoid medicinal chemistry in recent years has identified ligands highly specific for one of the three RAR subtypes (RAR-alpha) and for the RXR family of receptors, as well as antagonists for the RARs, RARalpha and the RXRs. Structure-activity relationships among the novel retinoid classes are reviewed along with potential therapeutic activities and side effects. RAR-alpha specific retinoids inhibit cancer cell growth but lack other retinoid toxicities, including skin irritation now ascribed to RAR-gama. RXR-specific retinoids lower blood glucose in animal models of type 2 diabetes albeit with a potential for mild hypothyroidism. Function-selective retinoids, especially a class of RAR antagonists called inverse agonists, have unexpected gene regulatory activity. Given the diverse properties and tissue distributions of the retinoid receptors, synthesis of additional classes of receptor-specific and function-selective ligands has the potential to produce novel therapeutic applications.

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Mitogenic effect of retinoid X receptor agonists in rat liver

Cited by 25 publications

References 28 publications

Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors

Mimetics of Caloric Restriction Include Agonists of Lipid-activated Nuclear Receptors

Overlapping Transcriptional Programs Regulated by the Nuclear Receptors Peroxisome Proliferator-Activated Receptor α, Retinoid X Receptor, and Liver X Receptor in Mouse Liver

Therapeutic Applications for Ligands of Retinoid Receptors

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