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      The Protective Role of Pregnane X Receptor in Lipopolysaccharide/D-galactosamine-induced Acute Liver Injury

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          Abstract

          The pregnane x receptor (PXR) is a nuclear receptor transcription factor regulating drug-metabolizing enzymes and transporters that facilitate xenobiotic and endobiotic detoxification. Recent studies demonstrate that PXR is important in abrogating intestinal tissue damage. This study examines the role of PXR in lipopolysaccharide (LPS)/D-galactosamine (GalN)-induced acute liver injury using wild type and PXR-null mice. LPS/GalN-treated PXR-null mice had greater increases of alanine aminotransferase (ALT), hepatocyte apoptosis, necrosis, and hemorrhagic liver injury than wild type mice. LPS/GalN-mediated phosphorylation of JNK1/2 and ERK1/2 was differentially regulated in wild type and PXR-null mice. Importantly, LPS/GalN-induced hepatic Stat3 survival signaling was impaired and early activation of Jak2 was delayed in PXR-null mice. Expression levels of pro-survival proteins Bcl-xL and heme oxygenase-1 (HO-1), which are downstream of Stat3, were substantially lower in PXR-null than wild type mouse livers after LPS/GalN treatment. Autophagy is also involved in LPS/GalN-induced liver injury. Lack of PXR resulted in a significant reduction of LC3B-I, -II as well as Beclin-1 protein levels after LPS/GalN treatment. Taken together, PXR is a critical hepatoprotective factor. Increases of LPS/GalN-induced hepatocyte apoptosis and liver injury in PXR-null mice are due to deregulated MAP kinase activation as well as delayed Jak2/Stat3 activation, which lead to a compromise in defense mechanisms that involve Bcl-xL-, HO-1, and autophagy-mediated pathways.

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          Most cited references 54

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          Stat3 as an oncogene.

          STATs are latent transcription factors that mediate cytokine- and growth factor-directed transcription. In many human cancers and transformed cell lines, Stat3 is persistently activated, and in cell culture, active Stat3 is either required for transformation, enhances transformation, or blocks apoptosis. We report that substitution of two cysteine residues within the C-terminal loop of the SH2 domain of Stat3 produces a molecule that dimerizes spontaneously, binds to DNA, and activates transcription. The Stat3-C molecule in immortalized fibroblasts causes cellular transformation scored by colony formation in soft agar and tumor formation in nude mice. Thus, the activated Stat3 molecule by itself can mediate cellular transformation and the experiments focus attention on the importance of constitutive Stat3 activation in human tumors.
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            Carbon monoxide has anti-inflammatory effects involving the mitogen-activated protein kinase pathway.

            The stress-inducible protein heme oxygenase-1 provides protection against oxidative stress. The anti-inflammatory properties of heme oxygenase-1 may serve as a basis for this cytoprotection. We demonstrate here that carbon monoxide, a by-product of heme catabolism by heme oxygenase, mediates potent anti-inflammatory effects. Both in vivo and in vitro, carbon monoxide at low concentrations differentially and selectively inhibited the expression of lipopolysaccharide-induced pro-inflammatory cytokines tumor necrosis factor-alpha, interleukin-1beta, and macrophage inflammatory protein-1beta and increased the lipopolysaccharide-induced expression of the anti-inflammatory cytokine interleukin-10. Carbon monoxide mediated these anti-inflammatory effects not through a guanylyl cyclase-cGMP or nitric oxide pathway, but instead through a pathway involving the mitogen-activated protein kinases. These data indicate the possibility that carbon monoxide may have an important protective function in inflammatory disease states and thus has potential therapeutic uses.
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              Embryonic lethality and liver degeneration in mice lacking the RelA component of NF-kappa B.

              NF-kappa B, which consists of two polypeptides, p50 (M(r) 50K) and p65/RelA (M(r) 65K), is thought to be a key regulator of genes involved in responses to infection, inflammation and stress. Indeed, although developmentally normal, mice deficient in p50 display functional defects in immune responses. Here we describe the generation of mice deficient in the RelA subunit of NF-kappa B. Disruption of the relA locus leads to embryonic lethality at 15-16 days of gestation, concomitant with a massive degeneration of the liver by programmed cell death or apoptosis. Embryonic fibroblasts from RelA-deficient mice are defective in the tumour necrosis factor (TNF)-mediated induction of messenger RNAs for I kappa B alpha and granulocyte/macrophage colony stimulating factor (GM-CSF), although basal levels of these transcripts are unaltered. These results indicate that RelA controls inducible, but not basal, transcription in NF-kappa B-regulated pathways.
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                Author and article information

                Journal
                0376617
                5462
                Lab Invest
                Laboratory investigation; a journal of technical methods and pathology
                0023-6837
                1530-0307
                18 September 2009
                7 December 2009
                February 2010
                1 August 2010
                : 90
                : 2
                : 257-265
                Affiliations
                [1 ]Department of Pharmacology, Toxicology and Therapeutics, University of Kansas School of Medicine, Kansas City, Kansas, 66160, USA
                [2 ] Department of Pathology and Laboratory Medicine, University of Kansas School of Medicine, Kansas City, Kansas, 66160, USA
                Author notes
                Corresponding author Yu-Jui Yvonne Wan, Ph.D. Professor of Pharmacology 3901 Rainbow Boulevard Department of Pharmacology, Toxicology and Therapeutics University of Kansas Medical Center Kansas City, Kansas, 66160, USA Ph: 913-588-9111 Fax: 913-588-7501 ywan@ 123456kumc.edu
                Article
                nihpa146477
                10.1038/labinvest.2009.129
                2814901
                19997066

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                Funding
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute on Alcohol Abuse and Alcoholism : NIAAA
                Funded by: National Center for Research Resources : NCRR
                Award ID: R01 CA053596-19 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute on Alcohol Abuse and Alcoholism : NIAAA
                Funded by: National Center for Research Resources : NCRR
                Award ID: R01 AA014147-05 ||AA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute on Alcohol Abuse and Alcoholism : NIAAA
                Funded by: National Center for Research Resources : NCRR
                Award ID: P20 RR021940-027768 ||RR
                Categories
                Article

                Pathology

                liver injury, pxr, map kinases, nuclear receptor, apoptosis, jak2/stat3

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