Nuclear receptors: mediators and modifiers of inflammation-induced cholestasis

Mulder, Jaap; Karpen, Saul J.; Tietge, Uwe J. F.; Kuipers, Folkert

doi:10.2741/3400

Cited by 17 publications

(16 citation statements)

References 289 publications

(402 reference statements)

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“…These transporters work together to import and secrete the various molecules that comprise bile, also allowing for processing of some of these components via intracellular enzymes and signaling molecules (see accompanying articles in this issue for details on the transporters and nuclear receptors that regulate bile formation, as well as roles in human dis-ease [1][2][3][4][5][6][7] ). The flux of bile acids, the main solute in bile, drives the majority of bile formation, whereas impairments of bile acid-dependent and bile acid-independent fractions of bile flow bring about cholestasis (see these recent reviews for details [8][9][10][11][12][13][14][15][16] ). In essence, how well these hepatobiliary transporters function relates directly to the amount and composition of bile they produce.…”

Section: Basic Aspects Of Inflammation In Cholestasismentioning

confidence: 99%

“…These locally produced cytokines, in turn, activate membrane receptors on hepatocytes and cholangiocytes that transduce intracellular signals leading to altered transporter expression and function. 12,15,22 In hepatocytes, downregulation of hepatic transport systems involved in bile acid uptake and excretion, as well as downregulation of phase I and phase II detoxification systems, result in impairment in bile formation, and accumulation of bile acids and toxins in liver and serum. 8,23 The proinflammatory LPS-induced cytokines of most interest in these pathways are those involved in the hepatic acute-phase response-tumor necrosis factor a (TNFa), interleukin-1 b (IL-1b), and interleukin-6 (IL-6).…”

Section: Basic Aspects Of Inflammation In Cholestasismentioning

confidence: 99%

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The Role of Inflammation in Cholestasis: Clinical and Basic Aspects

Kosters

Karpen²

2010

Semin Liver Dis

178

126

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Hepatobiliary transport systems are essential for the uptake and excretion of a variety of compounds including bile acids. Disruption and dysregulation of this excretory pathway results in cholestasis, leading to the intrahepatic accumulation of bile acids and other toxic compounds with progression of liver pathology. Cholestasis induced by inflammation is a common complication in patients with extrahepatic infections or inflammatory processes, generally referred to as sepsis-associated cholestasis. Microbial products, including endotoxin, induce signaling pathways within hepatocytes either directly, or through activation of pro-inflammatory cytokines, leading to rapid and profound reductions in bile flow. The expression and function of key hepatobiliary transporters are suppressed in response to inflammatory signaling. These pro-inflammatory signaling cascades lead to repressed expression and activity of a large number of nuclear transcriptional regulators, many of which are essential for maintenance of hepatobiliary transporter gene expression. Interestingly, recently discovered molecular crosstalk between bile acid activated nuclear receptors and pro-inflammatory nuclear mediators may provide new means of understanding adaptive processes within liver. All together, inflammation-induced cholestasis, and the effects of retained molecules in cholestasis on inflammatory signals, are interwoven in the liver, providing potential opportunities for research and therapeutics.

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Section: Basic Aspects Of Inflammation In Cholestasismentioning

confidence: 99%

Section: Basic Aspects Of Inflammation In Cholestasismentioning

confidence: 99%

The Role of Inflammation in Cholestasis: Clinical and Basic Aspects

Kosters

Karpen²

2010

Semin Liver Dis

178

126

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show abstract

“…This model predicts that proinflammatory cytokines, in turn, signal through their respective membrane receptors to suppress transporter expression and function (Geier et al, 2006;Lickteig et al, 2007;Mulder et al, 2009). Although the underlying mechanisms remain unclear, LPSinduced alteration of transporter function appears to be immunemediated and the direct cause of cholestasis.…”

Section: Introductionmentioning

confidence: 99%

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

Bodeman

Dzierlenga

Tally

et al. 2013

J Pharmacol Exp Ther

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Cholestasis results from interrupted bile flow and is associated with immune-mediated liver diseases. It is unclear how inflammation contributes to cholestasis. The aim of this study was to determine whether T and B cells contribute to hepatic transporter expression under basal and inflammatory conditions. C57BL/6J wild-type mice or strains lacking T, B, or both T and B cells were exposed to lipopolysaccharide (LPS) or saline, and livers were collected 16 hours later. Branched DNA signal amplification was used to assess mRNA levels of organic anion-transporting polypeptides (Oatp) 1a1, 1a4, and 1b2; organic cation transporter (Oct) 1; canalicular bile-salt export pump (Bsep); multidrug resistance-associated proteins (Mrp) 2 and 3; and sodium-taurocholate cotransporting polypeptide (Ntcp). Real-time polymerase chain reaction analysis was used to correlate changes of transporter expression with interleukin-1b (IL-1b), IL-6, IL-17A, IL-17F, tumor necrosis factor-a (TNF-a), and interferon-g expression in the liver. LPS treatment inhibited Bsep and Oct1 mRNA expression, and this was abrogated with a loss of T cells, but not B cells. In addition, the absence of T cells increased Mrp2 mRNA expression, whereas B cell deficiency attenuated Oatp1a4 mRNA in LPS-treated mice. Oatp1a1, Oatp1b2, Ntcp, and Mrp3 were largely unaffected by T or B cell deficiency. Lymphocyte deficiency altered basal and inflammatory IL-6, but not TNF-a or IL-1b, mRNA expression. Taken together, these data implicate lymphocytes as regulators of basal and inflammatory hepatic transporter expression and suggest that IL-6 signaling may play a critical role.

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“…Considering that any decrease in BSEP significantly contributes cholestasis development and possibly liver cancer (Mulder et al, 2009;Wang et al, 2011), this identifies SUMOylation as one of the potentially modifiable regulators of hepatobiliary function. Other inflammatory models (Cherrington et al, 2004;Le Vee et al, 2008;Wauters et al, 2010) have reported a significant reduction in BSEP expression during inflammation; however, technical experimental considerations precluded the combinatorial, prolonged testing of TNFa, GA, and CDCA, in our model system.…”

Section: Discussionmentioning

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

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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.

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Nuclear receptors: mediators and modifiers of inflammation-induced cholestasis

Cited by 17 publications

References 289 publications

The Role of Inflammation in Cholestasis: Clinical and Basic Aspects

The Role of Inflammation in Cholestasis: Clinical and Basic Aspects

Differential Regulation of Hepatic Organic Cation Transporter 1, Organic Anion-Transporting Polypeptide 1a4, Bile-Salt Export Pump, and Multidrug Resistance-Associated Protein 2 Transporter Expression in Lymphocyte-Deficient Mice Associates with Interleukin-6 Production

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

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