Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Comparisons between liver tissues and freshly isolated hepatocytes from IkkÎ²F/F and IkkÎ²Dhep (IkkÎ²-deleted) mice

ABSTRACT: CD74, a Type II membrane glycoprotein and MHC class II chaperone (Ii), is normally expressed by cells associated with the immune system. CD74 also forms heterodimers with CD44 to generate receptors to macrophage migration inhibitory factor (MIF), a proinflammatory cytokine. Following targeted Cre-mediated deletion of IkkÎ² in IkkÎ²DeltaHep mice (a strain highly susceptible to chemically-induced hepatotoxicity and hepatocarcinogenesis), CD74 is abundantly expressed by hepatocytes throughout liver acini (as detected by specific Western blots and immunohistochemical stains); it is not observed in either control IkkÎ²F/F hepatocytes or embryonic fibroblasts from IkkÎ²-/- mice. Constitutive CD74 expression in IkkÎ²DeltaHep hepatocytes is also accompanied by significantly augmented expression of CD44 and genes associated with antigen processing and host defense. These observations suggest that IkkÎ²DeltaHep hepatocytes might directly respond to MIF signaling, accounting partly for the enhanced susceptibility of IkkÎ²DeltaHep mice to hepatotoxins and hepatocarcinogens, and also might exhibit unusual immunological properties including antigen presentation. Total RNA samples were obtained from four 6-8 week-old male mice. The four RNA samples were processed as described in the PROTOCOLS section below.

ORGANISM(S): Mus musculus

SUBMITTER: Dr. Hyam Leffert

PROVIDER: E-GEOD-15476 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Targeted deletion of hepatocyte Ikkbeta confers growth advantages.

Koch Katherine S KS Maeda Shin S He Guobin G Karin Michael M Leffert Hyam L HL

Biochemical and biophysical research communications 20090124 2

Mice lacking hepatocyte IKKbeta (Ikkbeta(Delta hep)) are defective in TNFalpha-activation of hepatocellular transcription factor NF-kappaB, and highly susceptible to hepatotoxicity. Following diethylnitrosamine (DEN) exposure, Ikkbeta(Delta hep) mice develop more hepatocellular carcinoma (HCC) than control mice due partly to enhanced DEN-induced hepatocyte death. Here we show that Ikkbeta(Delta hep) hepatocytes display growth advantages over normal hepatocytes consisting of precocious PCNA and c ...[more]

PMID: 19171122

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Project description:Atherosclerosis is the underlying cause of myocardial infarction and ischemic stroke. It is a lipid-triggered inflammatory condition of arterial vessels driven by cytokines and chemokines. Chemokines that affect both vascular and metabolic pathologies are rare. Here we show that D-dopachrome tautomerase (D-DT)/macrophage migration inhibitory factor-2 (MIF-2), a paralog of the atherogenic cytokine MIF, is a novel atypical chemokine promoting athero-sclerotic plaque formation and hepatic lipid accumulation. Mif-2 deficiency and its pharma-cological blockade in hyperlipidemic atherogenic Apoe–/– mice protected against lesion formation and vascular inflammation in early and advanced atherogenesis. MIF-2 promoted monocyte migration and arrest on aortic endothelial monolayers, promoted B-cell recruitment, and increased foam cell formation. Employing biochemical and cellular assays, we identified CXCR4 as a novel receptor for MIF-2. Notably, Mif-2–/–Apoe–/– mice exhibited decreased plasma lipid levels, smaller livers, and reduced hepatic lipid accumulation compared to Apoe–/– mice. Comparison of the hepatic transcriptome and lipidome between Apoe–/– and Mif-2–/–Apoe–/– mice revealed a notable enrichment of lipogenesis-related pathways, triacylglycerides, diacylglycerides, and cholesterol esters in Mif-2-proficient mice. Mechanistic experiments in hepatocytes suggested that MIF-2 regulates activation of SREBP transcription factors to induce down¬stream lipogenic genes, while upstream, this pathway was mediated by the receptors CD74 and CXCR4, and PI3K/AKT but not AMPK signaling. Proximity ligation and FLIM-FRET multiphoton-microscopy indicated that CXCR4 and CD74 form a MIF-2-inducible heteromeric complex. Lastly, MIF-2 was found upregulated in unstable human carotid plaques from atherosclerotic patients undergoing carotid endarterectomy (CEA), suggesting a role for MIF-2 in advanced stages of athero¬sclerosis. Moreover, plasma concentrations of MIF-2 were increased in patients with coronary artery disease (CAD) and correlated with disease severity. Together, these data identify MIF-2 as a novel atherogenic chemokine and CXCR4 ligand associated with CAD that not only promotes lesion formation and vascular inflammation, but also affects hepatic lipogenesis in a CD74/CXCR4/SREBP-mediated manner. MIF-2 may thus be a novel player in atherosclerotic and metabolic disease.

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Dataset Information

Comparisons between liver tissues and freshly isolated hepatocytes from IkkÎ²F/F and IkkÎ²Dhep (IkkÎ²-deleted) mice

Publications

Targeted deletion of hepatocyte Ikkbeta confers growth advantages.

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