Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Ghose, Romi; Mulder, Jaap; Furstenberg, Richard J. von; Thevananther, Sundararajah; Kuipers, Folkert; Karpen, Saul J.

doi:10.1016/j.jhep.2006.09.008

Cited by 33 publications

(37 citation statements)

References 37 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…LPS in saline or saline alone. LPS in this dose range has been shown previously to induce cytokines and reduce expression of hepatic genes without inducing hepatic damage (Ghose et al, 2004(Ghose et al, , 2007. Livers were removed at the times indicated in the figure legends (1-16 h) after treatment.…”

Section: Methodsmentioning

confidence: 99%

See 1 more Smart Citation

Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Ghose

White²,

Guo³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

ABSTRACT:During inflammation, drug metabolism and clearance are altered due to suppression of hepatic drug-metabolizing enzyme (DME) genes and their regulatory nuclear receptors (NRs) [pregnane X receptor, constitutive androstane receptor, and retinoid X receptor ␣ (RXR␣)]. The bacterial endotoxin, lipopolysaccharide (LPS), induces expression of proinflammatory cytokines in the liver, which contribute to altered DME expression. LPS binds to the cell-surface receptor, Toll-like receptor 4 (TLR4), which initiates a signal transduction cascade, including recruitment of the Toll-interleukin 1 receptor domain-containing adaptor protein (TIRAP). However, the role of TLR4 and TIRAP in LPS-mediated regulation of hepatic DME gene expression is not known. Wild-type (C3HeB/FeJ), TLR4-mutant (C3H/HeJ), TIRAP ؉/؉ , and TIRAP ؊/؊ mice were injected i.p.with LPs. RNA levels of the major hepatic DME, Cyp3a11 and Ugt1a1, and the NRs were suppressed ϳ60 to 70% by LPS in wild-type but not in the TLR4-mutant mice. The nuclear protein levels of RXR␣ were reduced by LPS in wild-type but not in TLR4-mutant mice. Induction of hepatic cytokines (interleukin-1␤, tumor necrosis factor-␣, and interleukin-6), c-Jun N-terminal kinase, and nuclear factor-〉 was blocked in TLR4-mutant mice. Surprisingly, LPS had the same effect on cytokines, kinases, NRs, and DME genes in livers of both TIRAP

show abstract

Section: Methodsmentioning

confidence: 99%

“…Nuclear, cytoplasmic, and whole cell extracts were prepared as described previously (Ghose et al, 2004(Ghose et al, , 2007. The protein concentration was determined by BCA assay according to the manufacturer's protocol (Pierce Chemical, Rockford, IL).…”

Section: Methodsmentioning

confidence: 99%

Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Ghose

White²,

Guo³

et al. 2007

Drug Metab Dispos

Self Cite

View full text Add to dashboard Cite

show abstract

“…RARs can also interact with the p85α regulatory subunit of phosphoinositide 3-kinase (PI3K), leading to its activation in various cell types (15)(16)(17). Consistently, retinoid receptors are found to reside in the cytoplasm at certain stages during development (18,19) and in response to differentiation (14,20), apoptosis (21), and inflammation (22)(23)(24)(25)(26). Altered subcellular localization of retinoid receptors likely reflects changes in the cellular environment but may also play an active role in the regulation of cellular activities.…”

Section: Introductionmentioning

confidence: 95%

Oncogenic Potential of Retinoic Acid Receptor-γ in Hepatocellular Carcinoma

Yan

Zhang

et al. 2010

Cancer Research

View full text Add to dashboard Cite

Retinoic acid receptors (RAR; α, β, and γ), members of the nuclear receptor superfamily, mediate the pleiotropic effects of the vitamin A metabolite retinoic acid (RA) and derivatives (retinoids) in normal and cancer cells. Abnormal expression and function of RARs are often involved in the growth and development of cancer. However, the underlying molecular mechanisms remain largely elusive. Here, we report that levels of RARγ were significantly elevated in tumor tissues from a majority of human hepatocellular carcinoma (HCC) and in HCC cell lines. Overexpression of RARγ promoted colony formation by HCC cells in vitro and the growth of HCC xenografts in animals. In HepG2 cells, transfection of RARγ enhanced, whereas downregulation of RARγ expression by siRNA approach impaired, the effect of RA on inducing the expression of α-fetoprotein, a protein marker of hepatocarcinogenesis. In studying the possible mechanism by which overexpression of RARγ contributed to liver cancer cell growth and transformation, we observed that RARγ resided mainly in the cytoplasm of HCC cells, interacting with the p85α regulatory subunit of phosphatidylinositol 3-kinase (PI3K). The interaction between RARγ and p85α resulted in activation of Akt and NF-κB, critical regulators of the growth and survival of cancer cells. Together, our results show that overexpression of RARγ plays a role in the growth of HCC cells through nongenomic activation of the PI3K/Akt and NF-κB signaling pathways. Cancer Res; 70(6); 2285-95. ©2010 AACR.

show abstract

“…The liver orchestrates the systemic inflammatory response and the acute phase response-namely by producing acute phase proteins and by downregulating expression of many genes, including hepatobiliary transporters regulated by RXRa heterodimers (Beigneux et al, 2000;Ruminy et al, 2001;Zimmerman et al, 2006;Ghose et al, 2007). These inflammation-induced changes lead to toxin accumulation, further damaging liver integrity and function (Kosters and Karpen, 2010).…”

Section: Discussionmentioning

confidence: 99%

“…Retinoid X receptor a (RXRa), a member of the nuclear receptor (NR) superfamily (Germain et al, 2006), is essential for a range of physiologic functions in multiple tissues via crucial roles in development (Mark et al, 2009), metabolism (Shulman and Mangelsdorf, 2005), energy homeostasis (Imai, 2003;Grun and Blumberg, 2006), and inflammation (Ghose et al, , 2007Kuenzli et al, 2004;Zimmerman et al, 2006;Nunez et al, 2010). In liver, RXRa, the principal RXR isoform, plays a central role in liver physiology, particularly with respect to driving the expression of genes involved in intermediary metabolism, detoxification, as well as hepatobiliary transport and bile formation (Wagner et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Inflammatory Mediators Increase SUMOylation of Retinoid X Receptor α in a c-Jun N-Terminal Kinase–Dependent Manner in Human Hepatocellular Carcinoma Cells

Aguirre

Karpen

2013

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

Retinoid X receptor a [RXRa; nuclear receptor (NR)2B1] is a crucial regulator in the expression of a broad array of hepatic genes under both normal and pathologic conditions. During inflammation, RXRa undergoes rapid post-translational modifications, including c-Jun N-terminal kinase (JNK)-mediated phosphorylation, which correlates with a reduction in RXRa function. A small ubiquitin-like modifier (SUMO) acceptor site was recently described in human RXRa, yet the contributors, regulators, and consequences of SUMO-RXRa are not well understood. Inflammation and other stressors alter nuclear receptor function in liver and induce SUMOylation of several NRs as part of proinflammatory gene regulation, but linkages between these two pathways in liver, or for RXRa directly, remain unexplored. We sought to determine if inflammation induces SUMOylation of RXRa in human liver-derived (HuH-7) cells. Lipopolysaccharide, interleukin-1b, and tumor necrosis factor a (TNFa) rapidly and substantially stimulated SUMOylation of RXRa. Two RXRa ligands, 9-cis retinoic acid (9cRA) and LG268, induced SUMOylation of RXRa, whereas both inflammation-and ligand-induced SUMOylation of RXRa require the K108 residue. Pretreatment with 1,9-pyrazoloanthrone (SP600125), a potent JNK inhibitor, abrogates TNFa-and 9cRA-stimulated RXRa SUMOylation. Pretreatment with SUMOylation inhibitors markedly augmented basal expression of several RXRa-regulated hepatobiliary genes. These results indicate that inflammatory signaling pathways rapidly induce SUMOylation of RXRa, adding to the repertoire of RXRa molecular species in the hepatocyte that respond to inflammation. SUMOylation, a newly described post-translational modification of RXRa, appears to contribute to the inflammation-induced reduction of RXRaregulated gene expression in the liver that affects core hepatic functions, including hepatobiliary transport.

show abstract

Rosiglitazone attenuates suppression of RXRα-dependent gene expression in inflamed liver

Cited by 33 publications

References 37 publications

Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Regulation of Hepatic Drug-Metabolizing Enzyme Genes by Toll-Like Receptor 4 Signaling Is Independent of Toll-Interleukin 1 Receptor Domain-Containing Adaptor Protein

Oncogenic Potential of Retinoic Acid Receptor-γ in Hepatocellular Carcinoma

Inflammatory Mediators Increase SUMOylation of Retinoid X Receptor α in a c-Jun N-Terminal Kinase–Dependent Manner in Human Hepatocellular Carcinoma Cells

Contact Info

Product

Resources

About