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Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyte-selective inhibition of retinoid X receptor-? signalling during inflammation.

ABSTRACT: Inflammation leads to transcriptional downregulation of many hepatic genes, particularly those activated by retinoid X receptor-? (RXR?) heterodimers. Inflammation-mediated reduction of nuclear RXR? levels is a main factor in reduced nuclear receptor (NR)-regulated hepatic gene expression, eventually leading to cholestasis and liver damage.To investigate roles for RXR? in hepatic gene expression during inflammation, using two complementary mouse models: ligand activation of RXR?, and in mice expressing hepatocyte-specific expression of RXR? missing its DNA-binding domain (DBD; hs-Rxr??ex4(-/-) ).To activate RXR?, mice were gavage-fed with LG268 or vehicle for 5 days. To inhibit RXR? function, hs-Rxr??ex4(-/-) mice were used. All mice were injected intraperitoneally with lipopolysaccharides (LPS) or saline for 16 h prior to analysis of hepatic RNA, protein and NR-DNA binding.LG268 treatment attenuated the LPS-mediated reductions of several RXR?-regulated genes, coinciding with maintained RXR? occupancy in both Bsep and Ost? promoters. Lacking full hepatocyte RXR? function (hs-Rxr??ex4(-/-) mice) led to enhancement of LPS-mediated changes in gene expression, but surprisingly, maintenance of RNA levels of some RXR?-regulated genes. Investigations revealed that hs-Rxr??ex4(-/-) hepatocytes expressed an internally truncated, approximately 44 kDa, RXR?-form. DNA-binding capacity of NR heterodimers was equivalent in wild-type and hs-Rxr??ex4(-/-) livers, but reduced by LPS in both. Chromatin immunoprecipitation quantitative PCR revealed that RXR? occupancy to the Bsep RXR?:Farnesoid X Receptor site was reduced, but not absent, in hs-Rxr??ex4(-/-) livers.There are differential regulatory roles for hepatic RXR?, both in basal and inflammatory states, suggesting new and complex multidomain roles for RXR? in regulating hepatic gene expression. Moreover, there is an unexpected non-obligate role for the DBD of RXR?.

SUBMITTER: Kosters A

PROVIDER: S-EPMC3788689 | biostudies-other | 2012 Feb

REPOSITORIES: biostudies-other

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Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyte-selective inhibition of retinoid X receptor-α signalling during inflammation.

Kosters Astrid A Tian Feng F Wan Yu-Jui Yvonne YJ Karpen Saul J SJ

Liver international : official journal of the International Association for the Study of the Liver 20111101 2

<h4>Background</h4>Inflammation leads to transcriptional downregulation of many hepatic genes, particularly those activated by retinoid X receptor-α (RXRα) heterodimers. Inflammation-mediated reduction of nuclear RXRα levels is a main factor in reduced nuclear receptor (NR)-regulated hepatic gene expression, eventually leading to cholestasis and liver damage.<h4>Aim</h4>To investigate roles for RXRα in hepatic gene expression during inflammation, using two complementary mouse models: ligand acti ...[more]

PMID: 22098603

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Project description:Bisphenol A (BPA, 2,2-bis(4-hydroxyphenyl) propane) is a widely used industrial chemical. The extensive distribution of BPA in the environment poses risks to humans. However, the molecular mechanisms underlying BPA toxicity as well as its effective detoxification and elimination are not well understood. We have investigated specifically for BPA the notion raised in the literature that the optimal sensing, detoxification, and elimination of xenobiotics requires retinoid (natural derivatives and synthetic analogs of vitamin A) actions. The objective of the study was to explore how retinoids, both those stored in the liver and those originating from recent oral intake, help maintain an optimal xenobiotic detoxification response, affecting mRNA expression and activities of elements of xenobiotic detoxification system upon BPA administration to mice. Wild-type and mice lacking hepatic retinoid stores (Lrat-/-) were acutely treated with BPA (50?mg/kg body weight), with or without oral supplementation with retinyl acetate. Hepatic mRNA expression levels of the genes encoding nuclear receptors and their downstream targets involved in xenobiotic biotransformation, phase I and phase II enzyme activities, and levels of oxidative damage to cellular proteins and lipids in hepatic microsomes, mitochondria and cytosol, were assessed. BPA treatment induced hepatic activities needed for its detoxification and elimination in wild-type mice. However, BPA failed to induce these activities in the livers of Lrat-/- mice. Oral supplementation with retinyl acetate restored phase I and phase II enzyme activities, but accelerated BPA-induced oxidative damage through enhancement of non-mitochondrial ROS production. Thus, the activities of the enzymes involved in the hepatic elimination of BPA require hepatic retinoid stores. The extent of hepatic damage that arises from acute BPA intoxication is directly affected by retinoid administration during the period of BPA exposure and hepatic retinoid stores that have accumulated over the lifetime of the organism.

Dataset Information

Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyte-selective inhibition of retinoid X receptor-? signalling during inflammation.

Publications

Gene-specific alterations of hepatic gene expression by ligand activation or hepatocyte-selective inhibition of retinoid X receptor-α signalling during inflammation.

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