- Email: [email protected]
StARDl modulates hepatocellular carcinoma susceptibility to chemotherapy in vivo
POSTER PRESENTATIONS placebo was due to a significant increase of Firmicutes phylum (specifically genus members Butyricicoccus, Clostridium XI, Clostridium Xiva, Dorea, Sporobacter, Roseburia and Ruminococcus) compared with control and BDL rats treated with the bidifobacteria. The richness of microbial species, estimated by Chao1, Shannon and Simpson index, showed a significantly increased diversity in the intestinal microbiota of BDL group compared to the control group ( p = 0.04) (Fig.1). Administration of B. pseudocatenulatum CECT7765 reduced microbial diversity compared to placebo treated BDL rats ( p = 0.05).
membrane expression of GABA transporters GAT1 and GAT3 and increased extracellular GABA, associated with motor incoordination. Infliximab reduces peripheral inflammation, normalizes PGE2, IL-17, IL-6 and IL-10 levels, prevents neuroinflammation, reduces microglial and astrocytes activation and normalizes TNF-a and IL-1b. This is associated with normalization of AMPA receptors membrane expression in hippocampus and of spatial learning and memory. Infliximab also normalizes membrane expression of GAT1 and GAT3, extracellular GABA and motor coordination. Conclusions: This supports that peripheral inflammation contributes to spatial learning and motor coordination impairment in PCS rats. Treatment with anti-TNF-a could be a new therapeutic approach to improve cognitive function in patients with HE. SAT-061 StARD1 modulates hepatocellular carcinoma susceptibility to chemotherapy in vivo V. Ribas1, C. Garcia-Ruiz1, J. Fernandez-Checa1. 1IIBB-CSIC, Liver Unit Hospital Clinic, Ciberehd, Barcelona, Spain E-mail: [email protected]
Conclusions: The administration of B. pseudocatenulatum CECT7765 reduces both number and diversity of luminal bacteria in the BDL model of liver damage. These results support the role of B. pseudocatenulatum CECT7765 in contributing to reduction of intestinal bacterial overgrowth in experimental cirrhosis. SAT-060 Treatment with anti-TNFa reduces neuroinflammation and restores neurotransmission, learning and motor coordination in rats with hepatic encephalopathy S. Dadsetan1, T. Balzano1, J. Forteza2, A. Cabrera-Pastor1, L. Taoro-Gonzalez1, V. Hernandez-Rabaza1, A. Agusti3, C. Montoliu3, M. Llansola1, V. Felipo1. 1Laboratory of Neurobiology, Centro de Investigacion Principe Felipe; 2Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular. Centro Investigación Príncipe Felipe/ Universidad Católica; 3INCLIVA, Valencia, Spain E-mail: [email protected] Background and Aims: Inflammation contributes to cognitive impairment in patients with minimal hepatic encephalopathy (MHE). How peripheral inflammation leads to cognitive impairment remains unclear. In animal models, neuroinflammation mediates cognitive impairment. We hypothesized that in rats with HE: (1) peripheral inflammation is a main contributor to neuroinflammation; (2) neuroinflammation in hippocampus impairs spatial learning by altering glutamatergic neurotransmission; (3) neuroinflammation in cerebellum impairs motor coordination by altering GABAergic neurotransmission; (4) reducing peripheral inflammation with infliximab (anti-TNF-a) would reduce neuroinflammation; (5) this would normalize neurotransmission, learning and motor coordination. The aim was to assess these hypotheses. Methods: We analyzed in rats with portacaval shunt (PCS), treated or not with infliximab: (a) peripheral inflammation: E2, IL10, IL-17 and IL-6; (b) neuroinflammation in hippocampus and cerebellum: microglial activation and content of TNF-a and IL-1b; (c) AMPA and NMDA receptors membrane expression in hippocampus; (d) extracellular GABA and membrane expression of GABA transporters in cerebellum; (e) spatial learning in the Radial and Morris water mazes; (f ) motor coordination in the beam walking. We assessed the effects of infliximab on the above parameters. Results: PCS rats show increased serum prostaglandin E2, IL-17 and IL-6 and reduced IL-10. PCS rats also show microglial and astrocytes activation and increased TNF-a and IL-1b in hippocampus and cerebellum. This was associated with altered AMPA and NMDA receptors membrane expression in hippocampus and impaired spatial learning and memory. In cerebellum PCS rats show altered
Background and Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide and a dramatic complication of advanced liver disease. Previous findings showed that obesity and hepatic steatosis promotes tumorigenesis, underlying the effect of lipids and hypernutrition in liver disease. Cholesterol, and more specifically its trafficking to mitochondria through the protein StARD1, is an emerging factor in the progression of fatty liver disease. Moreover, mitochondrial cholesterol accumulation is antiapoptotic and protects mitochondria from outer membrane permeabilization and cell death in response to chemotherapy and hypoxia. Therefore, the aim of this study is to investigate the sensitivity of StARD1-deficient tumor cells to chemotherapy treatment in an in vivo model of HCC. Methods: Mice with specific deletion of StARD1 (StARD1Δhep) were generated in our laboratory by crossing StARD1 floxed mice with albumin-Cre transgenic mice (The Jackson Laboratory. StARD1Δhep and their littermates were injected i.p. with a single dose of diethylnitrosamine (DEN) at 14 days of age. 30 days later, mice were fed with high fat diet (HFD, 60% calories from fat) containing cholesterol (0.5%) (HFCD) for 6 months. After that period animals were given two doses of 5 mg/Kg of doxorubicin in 5 days and animals were sacrificed 24 hours after the second dose. Liver samples were processed to detect proliferation, apoptosis and tumor markers by western blotting, IHC and qRT-PCR. Results: HFCD feeding to StARD1floxed mice increased and accelerated DEN-induced HCC prevalence compared to mice fed the HFD diet. Tumorogenesis was slightly reduced in StARD1Δhep when compared to StARD1floxed as shown by the multiplicity (average of tumors/ mice) and tumor burden (average area of tumors/mice) observed after 6 months of HFCD feeding. However, chemotherapy treatment induced a greater degree of cell death in tumors of StARD1Δhep showed by the induction of cell death markers in tumor cells such as caspase activation and TUNEL staining. Conclusions: Deletion of StARD1 function in HCC sensitizes tumor cells to cell death initiation by chemotherapy. Therefore, modulation of StARD1 in HCC could be a novel therapeutic strategy to enhance HCC treatments. SAT-062 New animal model of obesity and chronic liver disease to provide insights on non-alcoholic liver disease-induced hepatic encephalopathy O.-S. Rafael1, M. Tremblay1, M.-A. Clément1, M. Ocana-Sanchez2, C.F. Rose1. 1Department of Medicine, Hepato-Neuro Laboratory, CRCHUM, Universite de Montreal, Montreal, Canada; 2Neuroethology, University of Veracruz, Xalapa, Mexico E-mail: [email protected]
Journal of Hepatology 2017 vol. 66 | S543–S750
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membrane expression of GABA transporters GAT1 and GAT3 and increased extracellular GABA, associated with motor incoordination. Infliximab reduces peripheral inflammation, normalizes PGE2, IL-17, IL-6 and IL-10 levels, prevents neuroinflammation, reduces microglial and astrocytes activation and normalizes TNF-a and IL-1b. This is associated with normalization of AMPA receptors membrane expression in hippocampus and of spatial learning and memory. Infliximab also normalizes membrane expression of GAT1 and GAT3, extracellular GABA and motor coordination. Conclusions: This supports that peripheral inflammation contributes to spatial learning and motor coordination impairment in PCS rats. Treatment with anti-TNF-a could be a new therapeutic approach to improve cognitive function in patients with HE. SAT-061 StARD1 modulates hepatocellular carcinoma susceptibility to chemotherapy in vivo V. Ribas1, C. Garcia-Ruiz1, J. Fernandez-Checa1. 1IIBB-CSIC, Liver Unit Hospital Clinic, Ciberehd, Barcelona, Spain E-mail: [email protected]
Conclusions: The administration of B. pseudocatenulatum CECT7765 reduces both number and diversity of luminal bacteria in the BDL model of liver damage. These results support the role of B. pseudocatenulatum CECT7765 in contributing to reduction of intestinal bacterial overgrowth in experimental cirrhosis. SAT-060 Treatment with anti-TNFa reduces neuroinflammation and restores neurotransmission, learning and motor coordination in rats with hepatic encephalopathy S. Dadsetan1, T. Balzano1, J. Forteza2, A. Cabrera-Pastor1, L. Taoro-Gonzalez1, V. Hernandez-Rabaza1, A. Agusti3, C. Montoliu3, M. Llansola1, V. Felipo1. 1Laboratory of Neurobiology, Centro de Investigacion Principe Felipe; 2Instituto Valenciano de Patología, Unidad Mixta de Patología Molecular. Centro Investigación Príncipe Felipe/ Universidad Católica; 3INCLIVA, Valencia, Spain E-mail: [email protected] Background and Aims: Inflammation contributes to cognitive impairment in patients with minimal hepatic encephalopathy (MHE). How peripheral inflammation leads to cognitive impairment remains unclear. In animal models, neuroinflammation mediates cognitive impairment. We hypothesized that in rats with HE: (1) peripheral inflammation is a main contributor to neuroinflammation; (2) neuroinflammation in hippocampus impairs spatial learning by altering glutamatergic neurotransmission; (3) neuroinflammation in cerebellum impairs motor coordination by altering GABAergic neurotransmission; (4) reducing peripheral inflammation with infliximab (anti-TNF-a) would reduce neuroinflammation; (5) this would normalize neurotransmission, learning and motor coordination. The aim was to assess these hypotheses. Methods: We analyzed in rats with portacaval shunt (PCS), treated or not with infliximab: (a) peripheral inflammation: E2, IL10, IL-17 and IL-6; (b) neuroinflammation in hippocampus and cerebellum: microglial activation and content of TNF-a and IL-1b; (c) AMPA and NMDA receptors membrane expression in hippocampus; (d) extracellular GABA and membrane expression of GABA transporters in cerebellum; (e) spatial learning in the Radial and Morris water mazes; (f ) motor coordination in the beam walking. We assessed the effects of infliximab on the above parameters. Results: PCS rats show increased serum prostaglandin E2, IL-17 and IL-6 and reduced IL-10. PCS rats also show microglial and astrocytes activation and increased TNF-a and IL-1b in hippocampus and cerebellum. This was associated with altered AMPA and NMDA receptors membrane expression in hippocampus and impaired spatial learning and memory. In cerebellum PCS rats show altered
Background and Aims: Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide and a dramatic complication of advanced liver disease. Previous findings showed that obesity and hepatic steatosis promotes tumorigenesis, underlying the effect of lipids and hypernutrition in liver disease. Cholesterol, and more specifically its trafficking to mitochondria through the protein StARD1, is an emerging factor in the progression of fatty liver disease. Moreover, mitochondrial cholesterol accumulation is antiapoptotic and protects mitochondria from outer membrane permeabilization and cell death in response to chemotherapy and hypoxia. Therefore, the aim of this study is to investigate the sensitivity of StARD1-deficient tumor cells to chemotherapy treatment in an in vivo model of HCC. Methods: Mice with specific deletion of StARD1 (StARD1Δhep) were generated in our laboratory by crossing StARD1 floxed mice with albumin-Cre transgenic mice (The Jackson Laboratory. StARD1Δhep and their littermates were injected i.p. with a single dose of diethylnitrosamine (DEN) at 14 days of age. 30 days later, mice were fed with high fat diet (HFD, 60% calories from fat) containing cholesterol (0.5%) (HFCD) for 6 months. After that period animals were given two doses of 5 mg/Kg of doxorubicin in 5 days and animals were sacrificed 24 hours after the second dose. Liver samples were processed to detect proliferation, apoptosis and tumor markers by western blotting, IHC and qRT-PCR. Results: HFCD feeding to StARD1floxed mice increased and accelerated DEN-induced HCC prevalence compared to mice fed the HFD diet. Tumorogenesis was slightly reduced in StARD1Δhep when compared to StARD1floxed as shown by the multiplicity (average of tumors/ mice) and tumor burden (average area of tumors/mice) observed after 6 months of HFCD feeding. However, chemotherapy treatment induced a greater degree of cell death in tumors of StARD1Δhep showed by the induction of cell death markers in tumor cells such as caspase activation and TUNEL staining. Conclusions: Deletion of StARD1 function in HCC sensitizes tumor cells to cell death initiation by chemotherapy. Therefore, modulation of StARD1 in HCC could be a novel therapeutic strategy to enhance HCC treatments. SAT-062 New animal model of obesity and chronic liver disease to provide insights on non-alcoholic liver disease-induced hepatic encephalopathy O.-S. Rafael1, M. Tremblay1, M.-A. Clément1, M. Ocana-Sanchez2, C.F. Rose1. 1Department of Medicine, Hepato-Neuro Laboratory, CRCHUM, Universite de Montreal, Montreal, Canada; 2Neuroethology, University of Veracruz, Xalapa, Mexico E-mail: [email protected]
Journal of Hepatology 2017 vol. 66 | S543–S750
S583