Abstract
BackgroundLipopolysaccharide (LPS) treatment of animals down-regulates the expression of hepatic genes involved in a broad variety of physiological processes, collectively known as the negative hepatic acute phase response (APR). Retinoid X receptor α (RXRα), the most highly expressed RXR isoform in liver, plays a central role in regulating bile acid, cholesterol, fatty acid, steroid and xenobiotic metabolism and homeostasis. Many of the genes regulated by RXRα are repressed during the negative hepatic APR, although the underlying mechanism is not known. We hypothesized that inflammation-induced alteration of the subcellular location of RXRα was a common mechanism underlying the negative hepatic APR.ResultsNuclear RXRα protein levels were significantly reduced (~50%) within 1–2 hours after low-dose LPS treatment and remained so for at least 16 hours. RXRα was never detected in cytosolic extracts from saline-treated mice, yet was rapidly and profoundly detectable in the cytosol from 1 hour, to at least 4 hours, after LPS administration. These effects were specific, since the subcellular localization of the RXRα partner, the retinoic acid receptor (RARα), was unaffected by LPS. A potential cell-signaling modulator of RXRα activity, c-Jun-N-terminal kinase (JNK) was maximally activated at 1–2 hours, coincident with maximal levels of cytoplasmic RXRα. RNA levels of RXRα were unchanged, while expression of 6 sentinel hepatic genes regulated by RXRα were all markedly repressed after LPS treatment. This is likely due to reduced nuclear binding activities of regulatory RXRα-containing heterodimer pairs.ConclusionThe subcellular localization of native RXRα rapidly changes in response to LPS administration, correlating with induction of cell signaling pathways. This provides a novel and broad-ranging molecular mechanism for the suppression of RXRα-regulated genes in inflammation.
Highlights
Lipopolysaccharide (LPS) treatment of animals down-regulates the expression of hepatic genes involved in a broad variety of physiological processes, collectively known as the negative hepatic acute phase response (APR)
We have shown that IL-1β treatment of HepG2 cells, or primary rat hepatocytes, leads to JNKdependent repression of nuclear binding activity of the sodium/ taurocholate cotransporting polypeptide (Ntcp) transactivator, Retinoid X receptor α (RXRα):regulated by various RXRα heterodimer pairs: Ntcp (RARα), with consequent downregulation of Ntcp promoter activity [8]
We investigated whether low dose LPS administration had an effect on the RNA levels of RXRα, six of its heterodimeric partners and small heterodimer partner (SHP)–all known to be involved in hepatic gene expression [25] (Fig. 2A)
Summary
Lipopolysaccharide (LPS) treatment of animals down-regulates the expression of hepatic genes involved in a broad variety of physiological processes, collectively known as the negative hepatic acute phase response (APR). LPS and LPS-induced cytokines have been implicated in the pathogenesis and progression of a variety of liver diseases, including cholestasis, as well as being principal mediators of the negative hepatic APR [3]. The cholestatic effect of LPS is primarily due to cytokine-mediated inhibition of the function and expression of hepatic genes encoding critical proteins involved in bile formation and transport (reviewed in [4]). These hepatocellular transporters include the basolateral sodium/taurocholate cotransporter (Ntcp/Slc10a1) and organic anion transporting proteins (Oatp1/Slc21a1), as well as the canalicular multispecific organic anion exporter (Mrp2/Abcc2) and the bile salt export protein (Bsep/Abcb). Transcriptional down-regulation of the principal hepatic bile acid importer, Ntcp contributes to the reduction in bile acid uptake by hepatocytes in inflammation, whereas reduced Mrp expression leads to impaired excretion of conjugated bilirubin, glutathione and other organic anions into bile [5,6]
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