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894A AASLD ABSTRACTS HEPATOLOGY, October, 2015 preps were enriched by rapid adherence. Purity of KCs was assessed by RT-PCR and FACS for CD68, CD14, TLR4, CD3, and CD31. Primary KCs were infected with HIV-BaL (MOI=0.1) or mock infected and supernatants were collected at serial time points for p24, a marker of HIV replication, and TGFβ1 ELISA. Pro-fibrogenic effects of conditioned media from KCs on HSCs was assessed by qRT-PCR and specific effects of TGFβ1 were assessed using TGFβ1 blocking/neutralizing antibody. Recombinant TGFβ1 (10ng/mL) was used as a positive control. Results: 1) HIV Infection of KCs resulted in an 1.5 fold increase in TGFβ1 secretion (p
HEPATOLOGY, VOLUME 62, NUMBER 1 (SUPPL) AASLD ABSTRACTS 895A sustained to be increased in TAA+Vector group at week 3 whereas TAA+Relaxin rats had suppressed TIMP-2 expression by then. Liver α-smooth muscle actin (α-SMA) mRNA in both TAA+Vector and TAA+Relaxin rats was increased after 3 days but reversed to the normal level at week 3. Analysis of TGFβ and MMP9 mRNA demonstrated the similar pattern. Conclusions: A single adenoviral delivery of relaxin in the liver attenuated established hepatic fibrosis by suppressing collagen cross-links and enhancing collagen degradation. Disclosures: The following authors have nothing to disclose: Jung Il Lee, Ja Kyung Kim, Hye Young Chang, Kwan Sik Lee 1400 Galectin-1 promotes the activation of hepatic stellate cell and liver fibrosis through glycosylation-dependent interactions Ming-Heng Wu; Graduate Institute of Translational Medicine, College of Medical Sciences and Technology, Taipei Medical University, Taipei, Taiwan The activation of hepatic stellate cell (HSC) is a rate-limiting step in hepatic fibrosis. Therefore, developing approaches to destroy or normalize activated HSCs is important for liver fibrosis therapy. The coevolution of cell-surface glycans and glycan-binding proteins regulate the progression of physiologic and pathologic processes but this issue has not been well addressed in HSC activation and liver fibrosis. Here, we reported that galectin-1 (Gal-1), a β-galactoside binding protein, was highly expressed in the fibrotic livers. Gal-1 binding glycans [β1,6 N-acetylglucosamine-branched N-glycans and poly-N-acetylactosamine (LacNAc)] were highly presented in activated HSCs and facilitated Gal-1 binding. In contrast, the amounts of α2,6 sialylation glycan (which masks the Gal1 binding glycan) is lower in activated HSCs than in quiescent HSCs. Two glycosyltransferases, Mgat5 (N-acetylglucosaminyltransferase 5) and GCNT1 (core 2 N-acetylglucosaminyltransferase 1), mediated N- and O-glycans were required for Gal-1 stimulated migration and activation of HSCs. In addition, Gal-1 regulated PDGF and TGF-β1 induced signaling and HSC activation through interacting with neuropilin-1 (NRP-1). Using a mouse model, we found that thioacetamide (TAA), an organosulfur compounds, induced liver fibrosis was attenuated in Gal-1 null mice. In summary, our results demonstrated that the crucial role of Gal-1 in HSC activation and liver fibrosis. Strategies that disrupt the Gal-1/NRP-1 interactions could be developed for liver fibrosis therapy. Disclosures: The following authors have nothing to disclose: Ming-Heng Wu 1401 TRPC6 Channels Contribute to Hepatic Stellate Cell Activation Leading to Liver Fibrosis Kyu-Hee Hwang, Ji-Hee Kim, Soo-Jin Kim, Kyu-Sang Park, Seung- Kuy Cha; Physiology, Yonsei University Wonju College of Medicine, Wonju, Korea (the Republic of) Activation of hepatic stellate cells (HSCs) is a main cause of liver cirrhosis and portal hypertension. In response to injury, HSCs are activated by diverse hormones and growth factors such as angiotensin II and endothelin-1 whose receptors are linked to phospholipase activation leading to Ca 2+ influx termed receptor-operated Ca 2+ entry (ROCE). The Ca 2+ -mediated signaling pathways are implicated either directly or indirectly in activation of HSCs causing de novo expression of a-smooth muscle actin (αSMA) and/or profibrotic ligand TGFβ. However, the molecular identity and underlying mechanism of ROCE involving HSC activation are ill-defined. Here, we report that TRPC6 channel is a predominant molecular component of ROCE mediating HSC activation. Among TRPC sub-family, the TRPC6 expression was significantly increased in the bile duct ligation- and TAA-induced liver fibrosis animal models. Functionally, TRPC6-stimulated Ca 2+ influx was confirmed by specific blockade of TRPC6 with the siRNA against Trpc6 and pharmacological inhibitor SKF96365 in cultured human HSCs. Furthermore, overexpression of TRPC6 by gene delivery in mouse liver induced de novo expression of αSMA and TGFβ suggesting that TRPC6-mediated Ca 2+ influx may involve in HSC activation and liver fibrosis. These results provide a new perspective on the pathogenesis of liver fibrosis and may provide clues to treatment of the liver cirrhosis. Disclosures: The following authors have nothing to disclose: Kyu-Hee Hwang, Ji-Hee Kim, Soo- Jin Kim, Kyu-Sang Park, Seung-Kuy Cha 1402 Targeting Activated Stromal Fibroblasts in Primary Sclerosing Cholangitis Anja Moncsek 1 , Achim Weber 2 , Beat Müllhaupt 1 , Joachim C. Mertens 1 ; 1 Gastroenterology and Hepatology, University Hospital Zürich, Zürich, Switzerland; 2 Surgical Pathology, University Hospital Zürich, Zürich, Switzerland Background: Primary Sclerosing Cholangitis (PSC) is a chronic cholestatic condition with diffuse biliary inflammation and fibrosis that can affect the whole biliary system. The disease has a progressive course and results in biliary cirrhosis with all its sequelae. PSC is also one of the main known risk factors for the development of cholangiocarcinoma (CCA). We have previously shown that activated stromal fibroblasts (ASF) in cholangiocarcinoma, which have been implicated in tumor progression and metastasis display an activated phenotype with increased sensitivity to apoptotic stimuli and can be selectively targeted with pro-apoptotic BH3 mimetics (Mertens et.al. Cancer Res 2013). However, the role of ASF in PSC and progression to CCA is not well understood. Thus, our aim was to characterize ASF in PSC and explore selective pro-apoptotic targeting of this cell population. Methods: Human PSC specimens were examined by histology, immunofluorescence, Western blot and qRT-PCR. The MDR2 -/- mouse model was employed for in vivo <strong>studies</strong>. Results: The PSC tissue specimens we examined contain an abundance of activated stromal fibroblasts. By immunofluorescence the stromal compartment stains positive for Tenascin C and Collagen I, while the stromal fibroblasts are positive for alpha smooth muscle actin (aSMA). This phenotype resembles ASF in CCA. We were able to confirm the phenotype of PSC-ASF by PCR. The MDR2 -/- mouse model of PSC develops a periductal and bridging fibrosis within 8 to 12 weeks. In analogy to previous experiments in a rat model of CCA, MDR2 -/- mice were treated with the pro-apoptotic BH3 mimetic navitoclax for 2 weeks. Assessment of liver fibrosis by Hydroxyproline assay and Sirius red staining demonstrated a reduction in fibrosis. Preliminary results revealed a reduction of activated stromal fibroblasts. Conclusions: ASF in PSC resemble stromal fibroblasts in cholangiocarcinoma and display apoptotic sensitization that could be targeted therapeutically. Disclosures: The following authors have nothing to disclose: Anja Moncsek, Achim Weber, Beat Müllhaupt, Joachim C. Mertens
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1000A AASLD ABSTRACTS HEPATOLOGY, O
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1312A AUTHOR INDEX HEPATOLOGY, Octo
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1366A CATEGORY INDEX HEPATOLOGY, Oc
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