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  • 1
    Keywords: RAT ; TANDEM MASS-SPECTROMETRY ; SIGNALING PATHWAYS ; LIPID RAFTS ; PARTIAL-HEPATECTOMY ; GLYCOSPHINGOLIPID SYNTHESIS ; HEPATIC STEATOSIS ; SPHINGOLIPIDS ; BETA-GLUCOSIDASE-2 ; GALACTOSYLCERAMIDE
    Abstract: BACKGROUND AND AIMS: Glycolipids have been shown to serve specialized functions in cell signalling, proliferation and differentiation processes, which are all important during liver regeneration. We previously generated beta-glucosidase 2 (GBA2) knockout mice that accumulate the glycolipid glucosylceramide in various tissues, including the liver. The present study addressed the role of GBA2-deficiency and subsequent glucosylceramide accumulation in liver regeneration. METHODS: Gba2 knockout and wild-type mice were subjected to two-third partial hepatectomy. Mice were sacrificed at different time points, blood was collected, and the remnant liver was removed. Glucosylceramide and ceramide were quantified using mass spectrometry from whole liver and isolated hepatocytes. Serum and hepatocytic supernatant of IL-6, TNF-alpha and TGF-beta levels were measured using ELISA. Cell signalling proteins were analysed using immunoblots. RESULTS: Regenerating liver after partial hepatectomy showed a significant increase of hepatic glucosylceramide in GBA2-deficient mice compared to controls. Accumulation of glucosylceramide was associated with a delay in liver regeneration and reduced serum levels of IL-6 and TNF-alpha. Furthermore, reduced IL-6 led to decreased expression of the phosphorylated form of the signal transducer and activator of transcription 3 (P-STAT3). CONCLUSIONS: We conclude that increased glucosylceramide affects cytokine- and growth factor-mediated signalling pathways during liver regeneration. Thus, the repression of IL-6/STAT3 signalling pathway seems to be one of the mechanisms for the delay of liver regeneration in GBA2-deficient mice.
    Type of Publication: Journal article published
    PubMed ID: 22764777
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  • 2
    Keywords: GROWTH ; IN-VITRO ; MODEL ; PROTEIN ; CELL-ADHESION ; ANGIOGENIC SWITCH ; ALTERNATIVELY ACTIVATED MACROPHAGES ; DYSPLASTIC NODULES ; SINUSOIDAL ENDOTHELIUM ; VESSEL COOPTION
    Abstract: BACKGROUND & AIMS: Hepatocellular carcinoma (HCC) is a malignant tumour that is characterized by extensive vascular remodelling and responsiveness to treatment with the anti-angiogenic multikinase inhibitor sorafenib. The aim was to study endothelial remodelling in HCC. METHODS: The murine inducible albumin-SV40-large T-antigen model and two tissue microarrays (TMA) with 295 tumourous and 83 peri-tumourous samples of 296 patients with HCC were analysed for expression of liver sinusoidal endothelial cell (LSEC)-specific marker proteins, stabilin-1 and stabilin-2, LYVE-1 and CD32b. RESULTS: LSEC marker proteins were sequentially lost during HCC progression in the murine HCC model being absent from tumour nodules larger than 800 mum in diameter. Similarly, the TMA analysis of human HCCs revealed loss of all four marker proteins in the majority of tumourous tissue samples. Preservation of LYVE-1 expression showed a significant correlation with low grading (G1). In corresponding peri-tumourous liver tissue, loss of all marker proteins was seen in a minor proportion of cases (34%) while the majority of cases retained expression of at least one of the marker proteins. Loss of stabilin-2 expression in peri-tumourous liver tissue of patients with HCC was significantly less likely to occur (38%) than loss of the other marker proteins (63-95%) and it was associated with significantly longer tumour-specific (P = 0.0523) and overall (P = 0.0338) survival. Loss of stabilin-2 may enhance survival in HCC by preventing endothelial-tumour cell adhesive interactions and microvascular invasion. CONCLUSIONS: In summary, endothelial transdifferentiation is a major pathogenic event in HCC development indicating a switch from vessel co-option/intussusceptive angiogenesis to sprouting angiogenesis.
    Type of Publication: Journal article published
    PubMed ID: 23870052
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  • 3
    Keywords: brain ; RECEPTOR ; CANCER ; EXPRESSION ; human ; DISEASE ; liver ; EPITHELIA ; FAMILY ; primary ; INDUCTION ; etiology ; PEPTIDES ; EPITHELIAL-CELLS ; MUCINS ; CELL-MIGRATION ; CHRONIC HEPATITIS ; CIRRHOSIS ; DEFENSE ; DIGESTIVE-TRACT ; HUMAN SPASMOLYTIC POLYPEPTIDE ; intrahepatic biliary tree,mucin,primary biliary cirrhosis,repair,trefol factor family
    Abstract: Background/Aim: Trefoil factor family (TFF)1,2,3 are involved in a homeostasis/repair process of mucosal epithelia. In this study, the significance of TIFF family and deleted in the malignant brain tumor-1 (DMBT1), a putative receptor of TFF2, in the intrahepatic biliary tree was investigated in normal and diseased livers. Materials and Methods: Expression of TFF1,2,3 and DMBT1 were examined immunohistochemically in primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), chronic viral hepatitis (CVH), extrahepatic biliary obstruction (EBO), and normal livers. Results: In normal livers, TFF1,3 and DMBT1 were infrequently detectable in large and rarely in small bile ducts, respectively. TFF2 was not detectable in large bile ducts. In large bile duct diseases (PSC and EBO), expression of TFF3 and DMBT1 were increased. In small bile duct diseases (PBC and CVH), expression of TFF2/DMBT1 was induced in moderately to severely damaged ducts irrespective of etiology. Conclusion: The intrahepatic biliary tree shows a site-characteristic expression and induction of TIFF 1,2,3 and DMBT1. In large bile ducts, TIFF 1,3 were constitutively expressed and increased in pathologic bile ducts. In small bile ducts, TFF2/DMBT1 is induced in damaged ducts irrespective of etiologies. However, the cytoprotective/repair property of TFF2/DMBT1 may not be enough to prevent the following bile duct loss in PBC
    Type of Publication: Journal article published
    PubMed ID: 15101998
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