412 results on '"Liver cells -- Physiological aspects"'
Search Results
2. Researcher from University of Nebraska Medical Center Describes Findings in Veterans (Hepatocyte-specific deletion of thromboxane-prostanoid receptor has protective effects on alcohol-associated liver disease)
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Liver cells -- Physiological aspects ,Thromboxanes -- Physiological aspects ,Prostanoids -- Physiological aspects ,Health - Abstract
2023 JUN 17 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Fresh data on veterans are presented in a new report. According to [...]
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- 2023
3. Research Results from Tianjin University Update Knowledge of Molecular Science (Protective Role of Hepassocin against Hepatic Endoplasmic Reticulum Stress in Mice)
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Liver cells -- Physiological aspects ,Endoplasmic reticulum -- Physiological aspects -- Models ,Stress (Physiology) -- Analysis ,Proteins -- Physiological aspects -- Identification and classification ,Health - Abstract
2022 DEC 3 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Research findings on molecular science are discussed in a new report. According [...]
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- 2022
4. Researchers from Graduate School of Medicine Report Details of New Studies and Findings in the Area of Liver Cancer (Gasdermin D-mediated Release of Il-33 From Senescent Hepatic Stellate Cells Promotes Obesity-associated Hepatocellular Carcinoma)
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Liver cells -- Physiological aspects ,Obesity -- Complications and side effects ,Interleukins -- Health aspects ,Hepatoma -- Risk factors -- Development and progression -- Models ,Health - Abstract
2022 DEC 3 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Investigators publish new report on Oncology - Liver Cancer. According to news [...]
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- 2022
5. Study Findings from Albert Einstein College of Medicine Provide New Insights into Gastroenterology (OR22-1 Temporal And Spatial Cellular Heterogeneity Of Hepatocyte Metabolism)
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Liver cells -- Physiological aspects ,Insulin resistance -- Development and progression ,Gluconeogenesis -- Genetic aspects -- Health aspects ,Cell metabolism -- Health aspects ,Health - Abstract
2022 NOV 26 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Current study results on gastroenterology have been published. According to news reporting [...]
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- 2022
6. New Peroxisome Proliferator-Activated Receptors Data Have Been Reported by Investigators at University of California San Diego (UCSD) (Selective Ppar Delta Agonist Seladelpar Suppresses Bile Acid Synthesis By Reducing Hepatocyte Cyp7a1 Via the ...)
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Agonists (Biochemistry) -- Research ,Liver cells -- Physiological aspects ,Bile acids -- Physiological aspects ,Biosynthesis -- Research ,Cellular signal transduction -- Research ,Liver diseases -- Drug therapy ,Cytochrome P-450 -- Physiological aspects ,Fibroblast growth factors -- Physiological aspects ,Health - Abstract
2022 JUL 30 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Research findings on Proteins - Peroxisome Proliferator-Activated Receptors are discussed in a [...]
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- 2022
7. New Study Findings from Hamad Bin Khalifa University Illuminate Research in Non-Alcoholic Fatty Liver Disease (Comparative Transcriptome Analysis Reveals That Exendin-4 Improves Steatosis in HepG2 Cells by Modulating Signaling Pathways Related ...)
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Liver cells -- Physiological aspects ,Lipid metabolism -- Health aspects ,Transcription factors -- Health aspects ,Health - Abstract
2022 JUN 18 (NewsRx) -- By a News Reporter-Staff News Editor at Obesity, Fitness & Wellness Week -- Data detailed on non-alcoholic fatty liver disease have been presented. According to [...]
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- 2022
8. New Data from University of Calgary Illuminate Research in Steroid Receptors (Cortisol Rapidly Facilitates Glucocorticoid Receptor Translocation to the Plasma Membrane in Primary Trout Hepatocytes)
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Liver cells -- Physiological aspects ,Biological sciences ,Health - Abstract
2023 MAR 7 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- Research findings on steroid receptors are discussed in a new report. According to news [...]
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- 2023
9. CXCL6 promotes human hepatocyte proliferation through the CXCR1-NFκB pathway and inhibits collagen I secretion by hepatic stellate cells
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Li, Zhenghong, Zhang, Qidi, Zhang, Qingqing, Xu, Mingyi, Qu, Ying, Cai, Xiaobo, and Lu, Lungen
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Cytokines -- Physiological aspects ,Liver cells -- Physiological aspects ,Cell proliferation -- Research ,Cell research ,Collagen -- Physiological aspects ,Transcription factors -- Physiological aspects ,Biological sciences - Abstract
Abstract: Hepatocyte proliferation and collagen I (COLI) secretion are important processes during liver regeneration. This study aimed to investigate the role of CXCL6 in hepatocyte proliferation and COLI secretion. Serum [...]
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- 2016
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10. Findings from Duke University Reveals New Findings on Cytoplasmic and Nuclear Receptors (Conserved Roles for Hnf4 Family Transcription Factors In Zebrafish Development and Intestinal Function)
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Liver cells -- Physiological aspects ,Intestines -- Physiological aspects ,Physiological research ,Transcription factors -- Physiological aspects ,Biological sciences ,Health - Abstract
2022 NOV 29 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- New research on Proteins - Cytoplasmic and Nuclear Receptors is the subject of a [...]
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- 2022
11. Researchers at Heilongjiang Bayi Agricultural University Publish New Study Findings on Green Fluorescent Proteins [Role of sortilin 1 (SORT1) on fatty acid-mediated cholesterol metabolism in primary calf hepatocytes]
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Agricultural research ,Glycoproteins -- Physiological aspects ,Liver cells -- Physiological aspects ,Calves -- Physiological aspects ,Fatty acids -- Physiological aspects ,Cholesterol metabolism -- Research ,Biological sciences ,Health - Abstract
2022 SEP 6 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- Fresh data on green fluorescent proteins are presented in a new report. According to [...]
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- 2022
12. Selection and evaluation of clinically relevant AAV variants in a xenograft liver model
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Lisowski, Leszek, Dane, Allison P., Chu, Kirk, Zhang, Yue, Cunningham, Sharon C., Wilson, Elizabeth M., Nygaard, Sean, Grompe, Markus, Alexander, Ian E., and Kay, Mark A.
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Liver cells -- Physiological aspects ,Animal models in research -- Usage ,Dependoviruses -- Physiological aspects ,Xenotransplantation -- Research ,Environmental issues ,Science and technology ,Zoology and wildlife conservation - Abstract
Recombinant adeno-associated viral (rAAV) vectors have shown early promise in clinical trials (1-3). The therapeutic transgene cassette can be packaged in different AAV capsid pseudotypes, each having a unique transduction profile. At present, rAAV capsid serotype selection for a specific clinical trial is based on effectiveness in animal models. However, preclinical animal studies are not always predictive of human outcome (4-8). Here, in an attempt to further our understanding of these discrepancies, we used a chimaeric human-murine liver model to compare directly the relative efficiency of rAAV transduction in human versus mouse hepatocytes invivo. As predicted from preclinical and clinical studies (4, 5, 8), rAAV2 vectors functionally transduced mouse and human hepatocytes at equivalent but relatively low levels. However, rAAV8 vectors, which are very effective in many animal models, transduced human hepatocytes rather poorly--approximately 20 times less efficiently than mouse hepatocytes. In light of the limitations of the rAAV vectors currently used in clinical studies, we used the same murine chimaeric liver model to perform serial selection using a human-specific replication-competent viral library composed of DNA-shuffled AAV capsids. One chimaeric capsid composed of five different parental AAV capsids was found to transduce human primary hepatocytes at high efficiency in vitro and in vivo, and provided species-selected transduction in primary liver, cultured cells and a hepatocellular carcinoma xenograft model. This vector is an ideal clinical candidate and a reagent for gene modification of human xenotransplants in mouse models of human diseases. More importantly, our results suggest that humanized murine models may represent a more precise approach for both selecting and evaluating clinically relevant rAAV serotypes for gene therapeutic applications., rAAV clinical trials have been hampered by unanticipated immunological responses and lower than expected levels of transgene product (5-8). For a single serotype there is little correlation between in vitro [...]
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- 2014
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13. Estrogen receptor alpha augments changes in hemostatic gene expression in HepG2 cells treated with estradiol and phytoestrogens
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Kelly, Lynne A., Seidlova-Wuttke, Dana, Wuttke, Wolfgang, O'Leary, John J., and Norris, Lucy A.
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Estradiol -- Dosage and administration ,Liver cells -- Physiological aspects ,Gene expression -- Physiological aspects ,Hemostasis -- Physiological aspects ,Isoflavones -- Health aspects ,Biological sciences ,Health ,Science and technology - Abstract
Phytoestrogens are popular alternatives to estrogen therapy however their effects on hemostasis in post-menopausal women are unknown. The aim of this study was to determine the effect of the phytoestrogens, genistein, daidzein and equol on the expression of key genes from the hemostatic system in human hepatocyte cell models and to determine the role of estrogen receptors in mediating any response seen. HepG2 cells and Hep89 cells (expressing estrogen receptor alpha (ERα)) were incubated for 24 h with 50 nM 17β-estradiol, genistein, daidzein or equol. Tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PA1-1), Factor VII, fibrinogen γ, protein C and protein S mRNA expression were determined using TaqMan PCR. Genistein and equol increased tPA and PAI-1 expression in Hep89 cells with fold changes greater than those observed for estradiol. In HepG2 cells (which do not express ERα), PAI-1 and tPA expression were unchanged. Increased expression of Factor VII was observed in phytoestrogen treated Hep89 cells but not in similarly treated HepG2s. Prothrombin gene expression was increased in equol and daidzein treated HepG2 cells in the absence of the classical estrogen receptors. These data suggest that phytoestrogens can regulate the expression of coagulation and fibrinolytic genes in a human hepatocyte cell line; an effect which is augmented by ERα. Keywords: Hemostasis Phytoestrogen Genistein ERα, Introduction Phytoestrogens have become increasingly popular as a 'natural' alternative to HT for treatment of menopausal symptoms and are thought to explain the lower risk of cardiovascular disease in Asia [...]
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- 2014
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14. JUNB/AP-1 controls IFN-γ during inflammatory liver disease
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Thomsen, Martin K., Bakiri, Latifa, Hasenfuss, Sebastian C., Hamacher, Rainer, Martinez, Lola, and Wagner, Erwin F.
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Liver cells -- Physiological aspects ,Hepatitis -- Research ,Liver cancer -- Research ,Health care industry - Abstract
Understanding the molecular pathogenesis of inflammatory liver disease is essential to design efficient therapeutic approaches. In hepatocytes, the dimeric transcription factor c-JUN/AP-1 is a major mediator of cell survival during hepatitis, although functions for other JUN proteins in liver disease are less defined. Here, we found that JUNB was specifically expressed in human and murine immune cells during acute liver injury. We analyzed the molecular function of JUNB in experimental models of hepatitis, including administration of concanavalin A (ConA) or α-galactosyl-ceramide, which induce liver inflammation and injury. Mice specifically lacking JUNB in hepatocytes displayed a mild increase in ConA-induced liver damage. However, targeted deletion of Junb in immune cells and hepatocytes protected against hepatitis in experimental models that involved NK/NKT cells. The absence of JUNB in immune cells decreased IFN-γ expression and secretion from NK and NKT cells, leading to reduced STAT1 pathwa y activation. Systemic IFN-γ treatment or adenovirus-based IRF1 delivery to Junb-deficient mice restored hepatotoxicity, and we demonstrate that Ifng is a direct transcriptional target of JUNB. These findings demonstrate that JUNB/AP-1 promotes cell death during acute hepatitis by regulating IFN-γ production in NK and NKT cells and thus functionally antagonizes the hepato-protective function of c-JUN/AP-1 in hepatocytes., Introduction Inflammation of the liver (hepatitis) is mostly triggered by viral infections. Intoxications (notably alcohol), autoimmune diseases, metabolic disorders, fatty liver disease, and hereditary disorders are also important contributors to [...]
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- 2013
15. New Findings Reported from Ghent University Describe Advances in Microbiology (Cytotoxic Effects of Alternariol, Alternariol Monomethyl-Ether, and Tenuazonic Acid and Their Relevant Combined Mixtures on Human Enterocytes and Hepatocytes)
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Liver cells -- Physiological aspects ,Intestines -- Physiological aspects ,Mycotoxins -- Physiological aspects ,Biological sciences ,Health - Abstract
2022 MAY 10 (NewsRx) -- By a News Reporter-Staff News Editor at Life Science Weekly -- New study results on microbiology have been published. According to news reporting originating from [...]
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- 2022
16. Podocyte-specific GLUT4-deficient mice have fewer and larger podocytes and are protected from diabetic nephropathy
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Guzman, Johanna, Jauregui, Alexandra N., Merscher-Gomez, Sandra, Maiguel, Dony, Muresan, Cristina, Mitrofanova, Alla, Diez-Sampedro, Ana, Szust, Joel, Yoo, Tae-Hyun, Villarreal, Rodrigo, Pedigo, Christopher, Molano, R. Damaris, Johnson, Kevin, Kahn, Barbara, Hartleben, Bjoern, Huber, Tobias B., Saha, Jharna, Burke, III, George W., Abel, E. Dale, Brosius, Frank C., and Fornoni, Alessia
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Liver cells -- Physiological aspects ,Carrier proteins -- Physiological aspects ,Diabetic nephropathies -- Prevention -- Physiological aspects ,Health - Abstract
Podocytes are a major component of the glomerular filtration barrier, and their ability to sense insulin is essential to prevent proteinuria. Here we identify the insulin downstream effector GLUT4 as a key modulator of podocyte function in diabetic nephropathy (DN). Mice with a podocyte-specific deletion of GLUT4 (G4 KO) did not develop albuminuria despite having larger and fewer podocytes than wild-type (WT) mice. Glomeruli from G4 KO mice were protected from diabetes-induced hypertrophy, mesangial expansion, and albuminuria and failed to activate the mammalian target of rapamycin (mTOR) pathway. In order to investigate whether the protection observed in G4 KO mice was due to the failure to activate mTOR, we used three independent in vivo experiments. G4 KO mice did not develop lipopolysaccharide-induced albuminuria, which requires mTOR activation. On the contrary, G4 KO mice as well as WT mice treated with the mTOR inhibitor rapamycin developed worse adriamycin-induced nephropathy than WT mice, consistent with the fact that adriamycin toxicity is augmented by mTOR inhibition. In summary, GLUT4 deficiency in podocytes affects podocyte nutrient sensing, results in fewer and larger cells, and protects mice from the development of DN. This is the first evidence that podocyte hypertrophy concomitant with podocytopenia may be associated with protection from proteinuria. Diabetes 2014;63:701-714 | DOI: 10.2337/db13-0752, Ever since it was demonstrated that insulin infusion can induce an acute transient increase in albumin excretion rate (1), the possibility of a direct effect of insulin signaling in glomerular [...]
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- 2014
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17. Protective effects of water extract of clam on normal and CCl4-induced damage in primary cultured rat hepatocytes
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Chi, H.M., Chou, S.T., Lin, S.C., Su, Z.Y., and Sheen, Lee-Yan
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Clams -- Research ,Clams -- Health aspects ,Antioxidants -- Research ,Antioxidants -- Health aspects ,Liver cells -- Research ,Liver cells -- Physiological aspects ,Glutathione -- Research ,Glutathione -- Health aspects ,Health - Published
- 2010
18. Lipoprotein profiles in SCID/uPA mice transplanted with human hepatocytes become human-like and correlate with HCV infection success
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Steenbergen, Rineke H.G., Joyce, Michael A., Lund, Garry, Lewis, Jamie, Chen, Ran, Barsby, Nicola, Zhu, Lin Fu, Tyrrell, D. Lorne J., and Kneteman, Norman M.
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Hepatitis C virus -- Physiological aspects ,Hepatitis C virus -- Research ,Low density lipoproteins -- Physiological aspects ,Low density lipoproteins -- Research ,Hepatitis C -- Risk factors ,Hepatitis C -- Development and progression ,Hepatitis C -- Genetic aspects ,Hepatitis C -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Biological sciences - Abstract
Although multiple determinants for hepatitis C virus (HCV) infection are known, it remains partly unclear what determines the human specificity of HCV infection. Presumably, the presence of appropriate entry receptors is essential, and this may explain why HCV is unable to infect nonhuman hepatocytes. However, using mice with chimeric human livers, we show in this study that the presence of human hepatocytes, and therefore human entry receptors, is not sufficient for HCV infection. In successfully transplanted SCID/Alb-uPA mice, infection with HCV is reliable only when ~70-80% of the liver consists of human hepatocytes. We show that chimeric mice, which are hard to infect with HCV, have significant groups of human hepatocytes that are readily infected with hepatitis B virus. Thus it is unlikely that the lack of infection with HCV can simply be attributed to low hepatocyte numbers. We investigated whether the humanization of lipoprotein profiles is positively associated with infection success. We show that the lipoprotein profiles of chimeric mice become more human-like at high levels of engraftment of human hepatocytes. This and expression of markers of human lipoprotein biosynthesis, human apolipoprotein B (ApoB) and cholesterol ester transfer protein (CETP), show a strong positive correlation with successful infection. Association of HCV in the blood of chimeric mice to ApoB-containing lipoproteins is comparable to association of HCV in patient serum and provides further support for a critical role for ApoB-containing lipoproteins in the infectious cycle of HCV. Our data suggest that the weakest link in the HCV infection chain does not appear to be the presence of human hepatocytes per se. We believe that HCV infection also depends on the presence of sufficient levels of human lipoproteins. apolipoprotein B; low-density lipoprotein; xenotransplantation; immunodeficient mouse; Flavivirus doi: 10.1152/ajpgi.00200.2010.
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- 2010
19. Pinus massoniana bark extract protects against oxidative damage in L-02 hepatic cells and mice
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Wang, Mei, Ma, Hong-Ling, Liu, Bing, Wang, Hong-Bin, Xie, Heng, Li, Ruo-Da, and Wang, Jin-Fa
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Pine -- Chemical properties ,Pine -- Health aspects ,Pine -- Research ,Oxidative stress -- Research ,Liver failure -- Prevention ,Liver failure -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Materia medica, Vegetable -- Research ,Plant extracts -- Research ,Health - Published
- 2010
20. High expression levels of putative hepatic stem/progenitor cell biomarkers related to tumour angiogenesis and poor prognosis of hepatocellular carcinoma
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Yang, Xin-Rong, Xu, Yang, Yu, Bin, Zhou, Jian, Qiu, Shuang-Jian, Shi, Guo-Ming, Zhang, Bo-Heng, Wu, Wei-Zhong, Shi, Ying-Hong, Wu, Bin, Yang, Guo-Huan Y, Ji, Yuan, and Fan, Jia
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Hepatoma -- Development and progression ,Hepatoma -- Patient outcomes ,Hepatoma -- Research ,Stem cells -- Identification and classification ,Liver cells -- Physiological aspects ,Liver cells -- Identification and classification ,Liver cells -- Research ,Biological markers -- Identification and classification ,Biological markers -- Research ,Health - Published
- 2010
21. Occult infection of peripheral B cells by hepatitis C variants which have low translational efficiency in cultured hepatocytes
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Durand, Tony, Di Liberto, Gaetana, Colman, Helene, Cammas, Anne, Boni, Sebastien, Marcellin, Patrick, Cahour, Annie, Vagner, Stephan, and Feray, Cyrille
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Hepatitis C virus -- Genetic aspects ,Hepatitis C virus -- Research ,B cells -- Genetic aspects ,B cells -- Physiological aspects ,B cells -- Research ,Liver cells -- Genetic aspects ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Health - Published
- 2010
22. Recombinant human hepassocin stimulates proliferation of hepatocytes in vivo and improves survival in rats with fulminant hepatic failure
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Li, Chang-Yan, Cao, Chuan-Zeng, Xu, Wang-Xiang, Cao, Meng-Meng, Fan Yang, Lan Dong, Miao Yu, Zhan, Yi-Qun, Gao, Ya-Bing, Wei Li, Wang, Zhi-Dong, Ge, Chang-Hui, Wang, Qing-Ming, Peng, Rui-Yun, and Yang, Xiao-Ming
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Rats -- Research ,Rats -- Health aspects ,Rattus -- Research ,Rattus -- Health aspects ,Liver failure -- Care and treatment ,Liver failure -- Patient outcomes ,Cell proliferation -- Research ,Cell proliferation -- Physiological aspects ,Liver cells -- Research ,Liver cells -- Physiological aspects ,Health - Published
- 2010
23. Cyclic AMP stimulates Mrp2 translocation by activating p38[alpha] MAPK in hepatic cells
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Schonhoff, Christopher M., Webster, Cynthia R.L., and Anwer, M. Sawkat
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Cyclic adenylic acid -- Physiological aspects ,Cyclic adenylic acid -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Mitogen-activated protein kinases -- Physiological aspects ,Mitogen-activated protein kinases -- Research ,Translocation (Genetics) -- Research ,Biological sciences - Abstract
Cyclic AMP (cAMP) induces translocation of multidrug resistant protein 2 (Mrp2) to the canalicular membrane and activates p38 MAPK in rat hepatocytes. In this study, we tested the hypothesis that cAMP-induced Mrp2 translocation may be mediated via p38 MAPK. Studies were conducted in rat hepatocytes and in a human hepatoma cell line, HUH-7. In rat hepatocytes, cAMP increased Mrp2 translocation and p38 MAPK activity. These effects of cAMP were inhibited by SB203580, an inhibitor of p38 MAPK. Wortmannin, a specific inhibitor of phosphoinositide-3-kinase (PI3K), did not inhibit cAMP induced activation of p38 MAPK, indicating PI3K-independent activation of p38 MAPK by cAMP. To further define the role of p38 MAPK, molecular approaches were used to up- or downregulate p38 MAPK activity in HUH-7 cells using constitutively active (CA) and dominant-negative (DN) MAPK kinase 3 and 6 (MKK3/6). MKK3/6 are upstream kinases responsible for the activation of p38 MAPK. Cells transfected with CAMKK6 showed increased p38 MAPK activity and MRP2 translocation compared with empty vector, cAMP-induced activation of p38 MAPK was inhibited in cells transfected with DNMKK3/6 and DNMKK3, but not with DNMKK6. DNMKK3/6 and DNMKK3 also inhibited cAMP-induced MRP2 translocation, cAMP selectively activated p38[alpha] MAPK in HUH-7 cells. Knockdown of p38[alpha] MAPK by short heterodimer RNA resulted in decreased level of p38 MAPK and failure of cAMP to stimulate MRP2 translocation. Taken together, these results suggest that cAMP-induced MRP2 translocation in hepatic cells is mediated via PI3K-independent and MKK3-mediated activation of p38[alpha] MAPK. p38 MAPK isoforms; rat hepatocytes; Huh-7 cells; MAPK kinase; phosphoinositide-3-kinase doi: 10.1152/ajpgi.00506.2009.
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- 2010
24. Characterisation of a stereotypical cellular and extracellular adult liver progenitor cell niche in rodents and diseased human liver
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Lorenzini, Stefania, Bird, Thomas G., Boulter, Luke, Bellamy, Christopher, Samuel, Kay, Aucott, Rebecca, Clayton, Elizabeth, Andreone, Pietro, Bernardi, Mauro, Golding, Mathew, Alison, Malcolm R., Iredale, John P., and Forbes, Stuart J.
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Liver cells -- Physiological aspects ,Liver cells -- Research ,Animal models in research -- Analysis ,Stem cell research ,Health - Published
- 2010
25. Signals from dying hepatocytes trigger growth of liver progenitors
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Jung, Youngmi, Witek, Rafal P., Syn, Wing-Kin, Choi, Steve S., Omenetti, Alessia, Premont, Richard, Guy, Cynthia D., and Diehl, Anna Mae
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Liver cells -- Physiological aspects ,Liver cells -- Research ,Cellular signal transduction -- Research ,Apoptosis -- Research ,Hedgehog proteins -- Physiological aspects ,Hedgehog proteins -- Research ,Health - Published
- 2010
26. Molecular determinants dictating cell surface expression of the human sodium-dependent vitamin C transporter-2 in human liver cells
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Subramanian, Veedamali S., Marchant, Jonathan S., and Said, Hamid M.
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Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Carrier proteins -- Physiological aspects ,Carrier proteins -- Genetic aspects ,Vitamin C -- Physiological aspects ,Vitamin C -- Genetic aspects ,Biological sciences - Abstract
Subramanian VS, Marchant JS, Said HM. Molecular determinants dictating cell surface expression of the human sodium-dependent vitamin C transporter-2 in human liver cells. Am J Physiol Gastrointest Liver Physiol 298: G267-G274, 2010. First published November 19, 2009; doi: 10.1152/ajpgi.00435.2009.--The human sodium-dependent vitamin C transporter-2 (hSVCT2) plays an important role in cellular accumulation of ascorbic acid in liver cells. However, little is known about the molecular determinants that direct hSVCT2 to the cell surface in hepatocytes. We addressed this issue using live cell imaging methods to resolve the distribution and trafficking of truncated or mutated hSVCT2 constructs in a cellular model of human hepatocytes, HepG2 cells. Whereas a full-length hSVCT2-yellow fluorescent protein (YFP) fusion protein was functionally expressed at the cell surface in HepG2 cells, serial truncation and mutation analysis demonstrated an essential role for both [NH.sub.2]and COOH-terminal sequence(s) for cell surface expression and function. Video-rate confocal imaging showed evidence of dynamic hSVCT2-YFP containing intracellular trafficking vesicles, the motility of which was impaired following disruption of microtubules using nocodazole. However, in a HepG2 cell line stably expressing hSVCT2-YFP at the cell surface, plasma membrane levels of hSVCT2 were unaffected by inhibition of microtubule-associated motor proteins; rather, surface expression of hSVCT2-YFP was increased following treatment with myosin inhibitors. Together, these results show that 1) both [NH.sub.2]- and COOH-terminal sequences are essential for proper localization of hSVCT2, 2) cell surface delivery is dependent on intact microtubules, and 3) peripheral microfilaments regulate insertion and retrieval of hSVCT2 into the plasma membrane. ascorbic acid; uptake; trafficking doi: 10.1152/ajpgi.00435.2009
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- 2010
27. Characterisation of the liver progenitor cell niche in liver diseases: potential involvement of Wnt and Notch signalling
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Spee, Bart, Carpino, Guido, Schotanus, Baukje A., Katoonizadeh, Azeam, Borght, Sara Vander, Gaudio, Eugenio, and Roskams, Tania
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Liver cells -- Physiological aspects ,Liver cells -- Research ,Liver diseases -- Development and progression ,Liver diseases -- Genetic aspects ,Liver diseases -- Research ,Wnt proteins -- Physiological aspects ,Wnt proteins -- Genetic aspects ,Wnt proteins -- Research ,Health - Published
- 2010
28. Hepatocyte nuclear factor 4(alpha) attenuates hepatic fibrosis in rats
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Yue, H.-Y., Yin, C., Hou, J.-L., Zeng, X., Chen, Y.-X., Zhong, W., Hu, P.-F., Deng, X., Tan, Y.-X., Zhang, J.-P., Ning, B.-F., Shi, J., Zhang, X., Wang, H.-Y., Lin, Y., and Xie, W.-F.
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Liver cirrhosis -- Development and progression ,Liver cirrhosis -- Research ,Liver cirrhosis -- Models ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Health - Published
- 2010
29. Liver fibrosis causes downregulation of miRNA-150 and miRNA-194 in hepatic stellate cells, and their overexpression causes decreased stellate cell activation
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Venugopal, Senthil K., Jiang, Joy, Kim, Tae-Hun, Li, Yong, Wang, Si-Si, Torok, Natalie J., Wu, Jian, and Zern, Mark A.
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Liver cells -- Physiological aspects ,Liver cells -- Research ,RNA -- Physiological aspects ,RNA -- Research ,Fibrosis -- Research ,Biological sciences - Abstract
Am J Physiol Gastrointest Liver Physiol 298: G101-G106, 2010. First published November 5, 2009; doi: 10.1152/ajpgi.00220.2009.--Activation of hepatic stellate cells (HSC) results in their proliferation and in the secretion of extracellular matrix (ECM) proteins, which leads to hepatic fibrosis, microRNAs (miRNAs) have been shown to regulate various cell functions, such as proliferation, differentiation, and apoptosis. Hence, we have analyzed the miRNAs that were differentially expressed in HSC isolated from sham-operated and bile duct-ligated rats. Expression of two miRNAs, miRNA-150 and miRNA-194, was reduced in HSC isolated from fibrotic rats compared with sham-operated animals. These two miRNAs were overexpressed in LX-2 cells, and their ability to inhibit cell proliferation, the expression of smooth muscle [alpha]-actin (SMA), a marker for activation, and collagen type I, a marker for ECM secretion, was determined. Overexpression of these two miRNAs resulted in a significant inhibition of proliferation (P < 0.05) and reduced SMA and collagen I levels compared with either untreated cells or nonspecific miRNA-expressing cells. Next, the protein targets of these two miRNAs were found using bioinformatics approaches. C-myb was found to be a target for miRNA-150, and rac 1 was found to be one of the targets for miRNA-194. Therefore, we studied the expression of these two proteins by overexpressing these two miRNAs in LX-2 cells and found that overexpression of miRNA-150 and miRNA-194 resulted in a significant inhibition of c-myb and rac 1 expression, respectively. We conclude that both miRNA-150 and miRNA-194 inhibit HSC activation and ECM production, at least in part, via inhibition of c-myb and rac 1 expression. c-myb; microRNA-150; microRNA-194; rac 1
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- 2010
30. Haematopoietic stem cell recruitment to injured murine liver sinusoids depends on (alpha)4(beta)1 integrin/VCAM-1 interactions
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Kavanagh, D.P.J., Durant, L.E., Crosby, H.A., Lalor, P.F., Frampton, J., Adams, D.H., and Kalia, N.
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Microcirculation -- Research ,Reperfusion injury -- Development and progression ,Reperfusion injury -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Integrins -- Physiological aspects ,Integrins -- Research ,Cell interaction -- Research ,Hematopoietic stem cells -- Transplantation ,Hematopoietic stem cells -- Research ,Health - Published
- 2010
31. Polysome trafficking of transcripts and microRNAs in regenerating liver after partial hepatectomy
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Kren, Betsy T., Wong, Phillip Y.-P., Shiota, Akira, Zhang, Xiaoxiao, Zeng, Yan, and Steer, Clifford J.
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Hepatectomy -- Physiological aspects ,Hepatectomy -- Genetic aspects ,Hepatectomy -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Tumor suppressor genes -- Physiological aspects ,Tumor suppressor genes -- Research ,Biological sciences - Abstract
Kren BT, Wong PY-P, Shiota A, Zhang X, Zeng Y, Steer CJ. Polysome trafficking of transcripts and microRNAs in regenerating liver after partial hepatectomy. Am J Physiol Gastrointest Liver Physiol 297: G1181-G1192, 2009. First published October l, 2009; doi: 10.1152/ajpgi.90636.2008.--Liver regeneration after 70% partial hepatectomy (PH) in rats induces >95% of hepatocytes to undergo two rounds of semisynchronous cell replication. Gene expression is controlled primarily by posttranscriptional processing, including changes in mRNA stability. However, the translational activity of a specific mRNA can also be modulated after PH, resulting in significant uncoupling of protein and transcript levels relative to quiescent liver for many genes including c-myc and p53. Although the precise mechanism by which this uncoupling occurs is unknown, the polysoreal association of mRNA and microRNA (miRNA) can significantly modulate rate of decay as well as translational activity. Thus we characterized the association of c-myc and p53 mRNAs and miRNAs in free and cytoskeleton- and membrane-bound polysome populations 3, 6, and 24 h after PH. The transcripts for c-myc and p53 were differentially distributed in the three discrete polysome populations, and this was dramatically modulated during liver regeneration. Nascent polysome-associated p53 and c-myc proteins were also differentially expressed in the free and cytoskeleton- and membrane-bound polysomes and significantly uncoupled from transcript levels relative to nonresected liver. At least 85 miRNAs were associated with the three polysome populations, and their abundance and distribution changed significantly during liver regeneration. These data suggest that posttranscriptional control of c-myc and p53 protein expression is associated with the translocation of transcripts between the different polyribosomes. The alteration of expression for the same transcript in different polysome populations may, in part, be due to the action of miRNAs. c-myc; liver regeneration; p53 doi: 10.1152/ajpgi.90636.2008
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- 2009
32. Cholecystokinin-58 and cholecystokinin-8 exhibit similar actions on calcium signaling, zymogen secretion, and cell fate in murine pancreatic acinar cells
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Criddle, David N., Booth, David M., Mukherjee, Rajarshi, MeLaughlin, Euan, Green, Gary M., Sutton, Robert, Petersen, Ole H., and Reeve, Joseph R., Jr.
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Mitochondrial DNA -- Physiological aspects ,Mitochondrial DNA -- Research ,Cholecystokinin -- Physiological aspects ,Cholecystokinin -- Genetic aspects ,Cellular signal transduction -- Physiological aspects ,Cellular signal transduction -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Biological sciences - Abstract
Criddle DN, Booth DM, Mukherjee R, McLaughlin E, Green GM, Sutton R, Petersen OH, Reeve JR Jr. Cholecystokinin-58 and cholecystokinin-8 exhibit similar actions on calcium signaling, zymogen secretion, and cell fate in murine pancreatic acinar cells. Am J Physiol Gastrointest Liver Physiol 297: G1085-G1092, 2009. First published October 8, 2009; doi: 10.1152/ajpgi.00119.2009.--The gastrointestinal hormone CCK exists in various molecular forms, with differences in bioactivity between the well-characterized CCK-8 and larger CCK-58 previously reported. We have compared the effects of these peptides on cytosolic calcium concentration ([[[Ca.sup.2+]].sub.c]), mitochondrial metabolism, enzyme secretion, and cell fate in murine isolated pancreatic acinar cells using fluorescence confocal microscopy and patch-clamp electrophysiology. CCK-58 (1-10 pM) induced transient, oscillatory increases of [[[Ca.sup.2+]].sub.c], which showed apical to basolateral progression and were associated with a rise of mitochondrial NAD(P)H. CCK-58 (10 pM) induced zymogen exocytosis in isolated cells and amylase secretion from isolated cells and whole tissues. Hyperstimulation with supraphysiological CCK-58 (5 nM) induced a single large increase of [[[Ca.sup.2+]].sub.c] that declined to a plateau, which remained above the basal level 20 min after application and was dependent on external [[Ca.sup.2+]] entry. In cells dispersed from the same tissues, CCK-8 induced similar patterns of responses to those of CCK-58, with oscillatory increases of [[[Ca.sup.2+]].sub.c] at lower (pM) concentrations and sustained responses at 5 nM. CCK-58 and CCK-8 exhibited similar profiles of action on cell death, with increases in necrosis at high CCK-58 and CCK-8 (10 nM) that were not significantly different between peptides. The present experiments indicate that CCK-8 and CCK-58 have essentially identical actions on the acinar cell at high and low agonist concentrations, suggesting an action via the same receptor and that the differences observed in an intact rat model may result from indirect effects of the peptides. Our data strengthen the argument that CCK-58 is an important physiological form of this gastrointestinal hormone. mitochondria; necrosis; apoptosis doi: 10.1152/ajpgi.00119.2009
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- 2009
33. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis
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Choi, Steve S., Omenetti, Alessia, Witek, Rafal P., Moylan, Cynthia A., Syn, Wing-Kin, Jung, Youngmi, Yang, Liu, Sudan, Debra L., Sicklick, Jason K., Michelotti, Gregory A., Rojkind, Marcos, and Diehl, Anna Mae
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Liver cirrhosis -- Genetic aspects ,Liver cirrhosis -- Development and progression ,Liver cirrhosis -- Research ,Cellular signal transduction -- Physiological aspects ,Cellular signal transduction -- Genetic aspects ,Cellular signal transduction -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Biological sciences - Abstract
Choi SS, Omenetti A, Witek RP, Moylan CA, Syn W, Jung Y, Yang L, Sudan DL, Sicklick JK, Michelotti GA, Rojkind M, Diehl AM. Hedgehog pathway activation and epithelial-to-mesenchymal transitions during myofibroblastic transformation of rat hepatic cells in culture and cirrhosis. Am J Physiol Gastrointest Liver Physiol 297:G1093-G1106, 2009. First published October 8, 2009; doi: 10.1152/ajpgi.00292.2009.--Myofibroblastic hepatic stellate cells (MF-HSC) are derived from quiescent hepatic stellate cells (Q-HSC). Q-HSC express certain epithelial cell markers and have been reported to form junctional complexes similar to epithelial cells. We have shown that Hedgehog (Hh) signaling plays a key role in HSC growth. Because Hh ligands regulate epithelial-to-mesenchymal transition (EMT), we determined whether Q-HSC express EMT markers and then assessed whether these markers change as Q-HSC transition into MF-HSC and whether the process is modulated by Hh signaling. Q-HSC were isolated from healthy livers and cultured to promote myofibroblastic transition. Changes in mRNA and protein expression of epithelial and mesenchymal markers, Hh ligands, and target genes were monitored in HSC treated with and without cyclopamine (an Hh inhibitor). Studies were repeated in primary human HSC and clonally derived HSC from a cirrhotic rat. Q-HSC activation in vitro (culture) and in vivo (C[Cl.sub.4]-induced cirrhosis) resulted in decreased expression of Hh-interacting protein (Hhip, an Hh antagonist), the EMT inhibitors bone morphogenic protein (BMP-7) and inhibitor of differentiation (Id2), the adherens junction component E-cadherin, and epithelial keratins 7 and 19 and increased expression of Gli2 (an Hh target gene) and mesenchymal markers, including the mesenchyme-associated transcription factors Lhx2 and Msx2, the myofibroblast marker [alpha]-smooth muscle actin, and matrix molecules such as collagen. Cyclopamine reverted myofibroblastic transition, reducing mesenchymal gene expression while increasing epithelial markers in rodent and human HSC. We conclude that Hh signaling plays a key role in transition of Q-HSC into MF-HSC. Our findings suggest that Q-HSC are capable of transitioning between epithelial and mesenchymal fates. bone morphogenetic protein-7; cyclopamine; fibrosis; proliferation; regeneration doi: 10.1152/ajpgi.00292.2009
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- 2009
34. Chronic oxidative stress sensitizes hepatocytes to death from 4-hydroxynonenal by JNK/c-Jun overactivation
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Singh, Rajat, Wang, Yongjun, Schattenberg, Jorn M., Xiang, Youqing, and Czaja, Mark J.
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Oxidative stress -- Research ,Oxidative stress -- Physiological aspects ,Fatty liver -- Research ,Fatty liver -- Physiological aspects ,Liver cells -- Research ,Liver cells -- Physiological aspects ,c-Jun N-terminal kinases -- Research ,c-Jun N-terminal kinases -- Physiological aspects ,Biological sciences - Abstract
Sustained activation of the c-Jun N[H.sub.2]-terminal kinase (JNK) signaling pathway mediates the development and progression of experimental diet-induced nonalcoholic fatty liver disease (NAFLD). Delineating the mechanism of JNK overactivation in the setting of a fatty liver is therefore essential to understanding the pathophysiology of NAFLD. Both human and experimental NAFLD are associated with oxidative stress and resultant lipid peroxidation, which have been proposed to mediate the progression of this disease from simple steatosis to steatohepatitis. The ability of oxidants and the lipid peroxidation product 4-hydroxynonenal (HNE) to activate JNK signaling suggested that these two factors may act synergistically to trigger JNK overactivation. The effect of HNE on hepatocyte injury and JNK activation was therefore examined in cells under chronic oxidant stress from overexpression of the prooxidant enzyme cytochrome P450 2E1 (CYP2E1), which occurs in NAFLD. CYP2E1-generated oxidant stress sensitized a rat hepatocyte cell line to death from normally nontoxic concentrations of HNE. CYP2E1-overexpressing cells underwent a more profound depletion of glutathione (GSH) in response to HNE secondary to decreased [gamma]-glutamylcysteine synthetase activity. GSH depletion led to overactivation of JNK/c-Jun signaling at the level of mitogenactivated protein kinase kinase 4 that induced cell death. Oxidant stress and the lipid peroxidation product HNE cause synergistic overactivation of the JNK/c-Jun signaling pathway in hepatocytes, demonstrating that HNE may not be just a passive biomarker of hepatic oxidant stress but rather an active mediator of hepatocellular injury through effects on JNK signaling. nonalcoholic fatty liver disease; glutathione; lipid peroxidation doi: 10.1152/ajpgi.00151.2009.
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- 2009
35. Formation of vitamin A lipid droplets in pancreatic stellate cells requires albumin
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Kim, N., Yoo, W., Lee, J., Kim, H., Lee, H., Kim, Y.-S., Kim, D.-U., and Oh, J.
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Vitamin A -- Physiological aspects ,Vitamin A -- Research ,Albumin -- Physiological aspects ,Albumin -- Research ,Fibrosis -- Development and progression ,Fibrosis -- Research ,Liver cells -- Physiological aspects ,Cell transformation -- Research ,Health - Published
- 2009
36. Oxygen-mediated enhancement of primary hepatocyte metabolism, functional polarization, gene expression, and drug clearance
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Kidambi, Srivatsan, Yarmush, Rubin S., Novik, Eric, Chao, Piyun, Yarmush, Martin L., and Nahmias, Yaakov
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Drug metabolism -- Research ,Gene expression -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Science and technology - Abstract
The liver is a major site for the metabolism of xenobiotic compounds due to its abundant level of phase I/II metabolic enzymes. With the cost of drug development escalating to over $400 million/ drug there is an urgent need for the development of rigorous models of hepatic metabolism for preclinical screening of drug clearance and hepatotoxicity. Here, we present a microenvironment in which primary human and rat hepatocytes maintain a high level of metabolic competence without a long adaptation period. We demonstrate that co-cultures of hepatocytes and endothelial cells in serum-free media seeded under 95% oxygen maintain functional apical and basal polarity, high levels of cytochrome P450 activity, and gene expression profiles on par with freshly isolated hepatocytes. These oxygenated co-cultures demonstrate a remarkable ability to predict in vivo drug clearance rates of both rapid and slow clearing drugs with an [R.sup.2] of 0.92. Moreover, as the metabolic function of oxygenated co-cultures stabilizes overnight, preclinical testing can be carried out days or even weeks before other culture methods, significantly reducing associated labor and cost. These results are readily extendable to other culture configurations including three-dimensional culture, bioreactor studies, as well as microfabricated co-cultures. drug discovery | liver metabolism | tissue engineering
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- 2009
37. Adiponectin-stimulated CXCL8 release in primary human hepatocytes is regulated by ERK1/ERK2, p38 MAPK, NF-[kappa]B, and STAT3 signaling pathways
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Wanninger, Josef, Neumeier, Markus, Weigert, Johanna, Bauer, Sabrina, Weiss, Thomas S., Schaffler, Andreas, Krempl, Corinna, Bleyl, Cornelia, Aslanidis, Charalampos, Scholmerich, Jurgen, and Buechler, Christa
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Protein hormones -- Physiological aspects ,Protein hormones -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Cellular signal transduction -- Physiological aspects ,Cellular signal transduction -- Research ,Chemokines -- Physiological aspects ,Chemokines -- Research ,Biological sciences - Abstract
Adiponectin is believed to exert hepatoprotective effects and induces CXCL8, a chemokine that functions as a survival factor, in vascular cells. In the current study, it is demonstrated that adiponectin also induces CXCL8 expression in primary human hepatocytes but not in hepatocellular carcinoma cell lines. Knock down of the adiponectin receptor (AdipoR) 1 or AdipoR2 by small-interfering RNA indicates that AdipoR1 is involved in adiponectin-stimulated CXCL8 release. Adiponectin activates nuclear factor (NF)-[kappa]B in primary hepatocytes and pharmacological inhibition of NF-[kappa]B, the p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase (ERK) 1/ERK2 reduces adiponectin-mediated CXCL8 secretion. Furthermore, adiponectin also activates STAT3 involved in interleukin (IL)-6 and leptin-mediated CXCL8 induction in primary hepatocytes. Inhibition of JAK2 by AG-490 does not abolish adiponectin-stimulated CXCL8, indicating that this kinase is not involved. Pretreatment of primary cells with 'STAT3 Inhibitor VI,' however, elevates hepatocytic CXCL8 secretion, demonstrating that STAT3 is a negative regulator of CXCL8 in these cells. In accordance with this assumption, IL-6, a well-characterized activator of STAT3, reduces hepatocytic CXCL8. Therefore, adiponectin-stimulated induction of CXCL8 seems to be tightly controlled in primary human hepatocytes, whereas neither NF-[kappa]B, STAT3, nor CXCL8 are influenced in hepatocytic cell lines. CXCL8 is a survival factor, and its upregulation by adiponectin may contribute to the hepatoprotective effects of this adipokine. adiponectin; hepatocyte; nuclear factor-[kappa]B; adiponectin receptor 1; STAT3; extracellular signal-regulated kinase; mitogen-activated protein kinase
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- 2009
38. Progress and future challenges in stem cell-derived liver technologies
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Dalgetty, Donna M., Medine, Claire N., Iredale, John P., and Hay, David C.
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Embryonic stem cells -- Health aspects ,Embryonic stem cells -- Genetic aspects ,Embryonic stem cells -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research ,Liver diseases -- Care and treatment ,Liver diseases -- Research ,Regenerative medicine -- Health aspects ,Biological sciences - Abstract
The emergence of regenerative medicine has led to significant advances in the identification and understanding of human stem cells and adult progenitor cells. Both cell populations exhibit plasticity and theoretically offer a potential source of somatic cells in large numbers. Such a resource has an important role to play in the understanding of human development, in modeling human disease and drug toxicity, and in the generation of somatic cells in large numbers for cell-based therapies. Presently, liver transplantation is the only effective treatment for end-stage liver disease. Although this procedure can be carried out with high levels of success, the routine transplant of livers is severely limited by organ donor availability. As a result, attention has focused on the ability to restore liver mass and function by alternative approaches ranging from the bioartificial device to transplantation of human hepatocytes. In this review we will focus on the generation of human hepatic endoderm from different stem/progenitor cell populations with a view to its utility in regenerative medicine. embryonic stem cell; function; hepatocyte; induced pluripotent stem cell
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- 2009
39. Possible implication of satellite cells in regenerative motoneuritogenesis: HGF upregulates neural chemorepellent Sema3A during myogenic differentiation
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Tatsumi, Ryuichi, Sankoda, Yoriko, Anderson, Judy E., Sato, Yusuke, Mizunoya, Wataru, Shimizu, Naomi, Suzuki, Takahiro, Yamada, Michiko, Rhoads, Robert P., Jr., Ikeuchi, Yoshihide, and Allen, Ronald E.
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Growth factors -- Physiological aspects ,Growth factors -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Motor neurons -- Physiological aspects ,Motor neurons -- Research ,Muscles -- Regeneration ,Muscles -- Physiological aspects ,Muscles -- Research ,Biological sciences - Abstract
Regenerative coordination and remodeling of the intramuscular motoneuron network and neuromuscular connections are critical for restoring skeletal muscle function and physiological properties. The regulatory mechanisms of such coordination remain unclear, although both attractive and repulsive axon guidance molecules may be involved in the signaling pathway. Here we show that expression of a neural secreted chemorepellent semaphorin 3A (Sema3A) is remarkably upregulated in satellite cells of resident myogenic stem cells that are positioned beneath the basal lamina of mature muscle fibers, when treated with hepatocyte growth factor (HGF), established as an essential cue in muscle fiber growth and regeneration. When satellite cells were treated with HGF in primary cultures of cells or muscle fibers, Sema3A message and protein were upregulated as revealed by reverse transcription-polymerase chain reaction and immunochemical studies. Other growth factors had no inductive effect except for a slight effect of epidermal growth factor treatment. Sema3A upregulation was HGF dose dependent with a maximum (about 7- to 8-fold units relative to the control) at 10-25 ng/ml and occurred exclusively at the early-differentiation stage, as characterized by the level of myogenin expression and proliferation (bromodeoxyuridine incorporation) of the cells. Neutralizing antibody to the HGF-specific receptor, c-met, did not abolish the HGF response, indicating that c-met may not mediate the Sema3A expression signaling. Finally, in vivo Sema3A was upregulated in the differentiation phase of satellite cells isolated from muscle regenerating following crush injury. Overall, the data highlight a heretofore unexplored and active role for satellite cells as a key source of Sema3A expression triggered by HGF, hence suggesting that regenerative activity toward motor innervation may importantly reside in satellite cells and could be a crucial contributor during postnatal myogenesis. hepatocyte growth factor; motor neuron; muscle regeneration; semaphorin 3A
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- 2009
40. The insulin/Akt pathway controls a specific cell division program that leads to generation of binucleated tetraploid liver cells in rodents
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Celton-Morizur, Severine, Merlen, Gregory, Couton, Dominique, Margall-Ducos, Germain, and Desdouets, Chantal
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Rodents -- Models ,Cell division -- Physiological aspects ,Cell division -- Research ,Cellular signal transduction -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research - Abstract
The formation of polyploid cells is part of the developmental program of several tissues. During postnatal development, binucleated tetraploid cells arise in the liver, caused by failure in cytokinesis. In this report, we have shown that the initiation of cytokinesis failure events and the subsequent appearance of binucleated tetraploid cells are strictly controlled by the suckling-to-weaning transition in rodents. We found that daily light/dark rhythms and carbohydrate intake did not affect liver tetraploidy. In contrast, impairment of insulin signaling drastically reduced the formation of binucleated tetraploid cells, whereas repeated insulin injections promoted the generation of these liver cells. Furthermore, inhibition of Akt activity decreased the number of cytokinesis failure events, possibly through the mammalian target of rapamycin signaling complex 2 (mTORC2), which indicates that the PI3K/Akt pathway lies downstream of the insulin signal to regulate the tetraploidization process. To our knowledge, these results are the first demonstration in a physiological context that insulin signaling through Akt controls a specific cell division program and leads to the physiologic generation of binucleated tetraploid liver cells., Introduction Polyploidy, the state of having greater than a diploid DNA content (tetraploid, octoploid, etc.), is a widespread physiological phenomenon observed particularly in plants, fish, and amphibians (1). Although it [...]
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- 2009
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41. Ketamine-induced hepatoprotection: the role of heme oxygenase-1
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Suliburk, James W., Ward, Jeremy L., Helmer, Kenneth S., Adams, Sasha D., Zuckerbraun, Brian S., and Mercer, David W.
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Cyclooxygenases -- Physiological aspects ,Cyclooxygenases -- Genetic aspects ,Cyclooxygenases -- Research ,Liver cells -- Injuries ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Ketamine -- Health aspects ,Biological sciences - Abstract
Lipopolysaccharide (LPS) causes hepatic injury that is mediated, in part, by upregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Ketamine has been shown to prevent these effects. Because upregulation of heme oxygenase-1 (HO-1) has hepatoprotective effects, as does carbon monoxide (CO), an end product of the HO-1 catalytic reaction, we examined the effects of HO-1 inhibition on ketamine-induced hepatoprotection and assessed whether CO could attenuate LPS-induced hepatic injury. One group of rats received ketamine (70 mg/kg ip) or saline concurrently with either the HO-1 inhibitor tin protoporphyrin IX (50 [micro]mol/kg ip) or saline. Another group of rats received inhalational CO (250 ppm over 1 h) or room air. All rats were given LPS (20 mg/kg ip) or saline 1 h later and euthanized 5 h after LPS or saline. Liver was collected for iNOS, COX-2, and HO-1 (Western blot), NF-[kappa]B and PPAR-[gamma] analysis (EMSA), and iNOS and COX-2 mRNA analysis (RT-PCR). Serum was collected to measure alanine aminotransferase as an index of hepatocellular injury. HO-1 inhibition attenuated ketamine-induced hepatoprotection and downregulation of iNOS and COX-2 protein. CO prevented LPS-induced hepatic injury and upregulation of iNOS and COX-2 proteins. Although CO abolished the ability of LPS to diminish PPAR-[gamma] activity, it enhanced NF-[kappa]B activity. These data suggest that the hepatoprotective effects of ketamine are mediated primarily by HO-1 and its end product CO. cyclooxygenase-2; inducible nitric oxide synthase; lipopolysaccharide; carbon monoxide; tin protoporphyrin IX
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- 2009
42. The protective role of HO-1 and its generated products (CO, bilirubin, and Fe) in ethanol-induced human hepatocyte damage
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Yao, Ping, Hao, Liping, Nussler, Natascha, Lehmann, Antje, Song, Fangfang, Zhao, Jing, Neuhaus, Peter, Liu, Liegang, and Nussler, Andreas
- Subjects
Liver cells -- Physiological aspects ,Liver cells -- Research ,Cytochrome P-450 -- Physiological aspects ,Cytochrome P-450 -- Research ,Liver diseases -- Risk factors ,Liver diseases -- Care and treatment ,Liver diseases -- Research ,Quercetin -- Health aspects ,Biological sciences - Abstract
It has been reported that naturally occurring quercetin exerts hepatoprotective effects through heme oxygenase-I (HO-I) induction. However, the precise mechanism of how ethanol-associated liver damage is counteracted by quercetin-enhanced HO-1 metabolism still remains unclear. To further decipher the protective role of quercetin on ethanol-induced liver damage, we treated human hepatocytes with quercetin and various (end) products of the HO-1 pathway. Our data clearly showed that quercetin treatment attenuated ethanol-induced damage, whereas hemoglobin and zinc protoporphyrin 9 (ZnPP) abolished such effects. Iron-II aggravated ethanol toxicity and was only partially reduced by quercetin. In contrast, carbon monoxide (CO) dose dependently inhibited ethanol-induced cytochrome P450 2E1 (CYP 2E1) activity and hepatotoxicity but had no influence on CYP 2E1 protein expression. Similarly, hemoglobin dramatically stimulated CYP 2E1 activity but not the protein expression in quercetin- and ethanol-cotreated hepatocytes. ZnPP significantly promoted CYP 2E1 protein expression in the presence and absence of CO treatment but inhibited ethanol-induced CYP 2E1 activation following CO incubation in quercetin- and ethanol-cotreated hepatocytes. These results suggested that quercetin virtually attenuated ethanol-derived oxidative damage via HO-1 induction. Heine degradation and CO release may mediate the protective effects through inhibiting ethanol-induced CYP 2E1 synthesis and enzymatic activity, respectively. quercetin; CYP 2E1; heine oxygenase-1; carbon monoxide
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- 2009
43. Capsid antigen presentation flags human hepatocytes for destruction after transduction by adeno-associated viral vectors
- Author
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Pien, Gary C., Basner-Tschakarjan, Etiena, Hui, Daniel J., Mentlik, Ashley N., Finn, Jonathan D., Hasbrouck, Nicole C., Zhou, Shangzhen, Murphy, Samuel L., Maus, Marcela V., Mingozzi, Federico, Orange, Jordan S., and High, Katherine A.
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T cells -- Health aspects ,T cells -- Research ,Genetic transformation -- Methods ,Hemophilia -- Risk factors ,Hemophilia -- Genetic aspects ,Hemophilia -- Care and treatment ,Hemophilia -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Genetic aspects ,Liver cells -- Research - Abstract
Adeno-associated virus (AAV) vectors are effective gene delivery vehicles mediating long-lasting transgene expression. Data from a clinical trial of AAV2-mediated hepatic transfer of the Factor IX gene (F9) into hemophilia B subjects suggests that CTL responses against AAV capsid can eliminate transduced hepatocytes and prevent long-term F9 expression. However, the capacity of hepatocytes to present AAV capsid--derived antigens has not been formally demonstrated, nor whether transduction by AAV sensitizes hepatocytes for CTL-mediated destruction. To investigate the fate of capsids after transduction, we engineered a soluble TCR for the detection of capsid-derived peptide:MHC I (pMHC) complexes. TCR multimers exhibited antigen and HLA specificity and possessed high binding affinity for cognate pMHC complexes. With this reagent, capsid pMHC complexes were detectable by confocal microscopy following AAV-mediated transduction of human hepatocytes. Although antigen presentation was modest, it was sufficient to flag transduced cells for CTL-mediated lysis in an in vitro killing assay. Destruction of hepatocytes was inhibited by soluble TCR, demonstrating a possible application for this reagent in blocking undesirable CTL responses. Together, these studies provide a mechanism for the loss of transgene expression and transient elevations in aminotransferases following AAV-mediated hepatic gene transfer in humans and a potential therapeutic intervention to abrogate these limitations imposed by the host T cell response., Introduction In the first phase I/II trial of hepatic gene transfer of adeno-associated virus 2 (AAV2) encoding Factor IX (AAV2-F9) in human hemophilia B subjects, transgene expression was demonstrable but [...]
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- 2009
44. In vivo dynamic metabolic imaging of obstructive cholestasis in mice
- Author
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Li, Feng-Chieh, Liu, Yuan, Huang, Guan-Tarn, Chiou, Ling-Ling, Liang, Jhih-Huei, Sun, Tzu-Lin, Dong, Chen-Yuan, and Lee, Hsuan-Shu
- Subjects
Cholestasis -- Risk factors ,Cholestasis -- Diagnosis ,Cholestasis -- Research ,Jaundice, Obstructive -- Risk factors ,Jaundice, Obstructive -- Diagnosis ,Jaundice, Obstructive -- Research ,Diagnostic imaging -- Usage ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Biological sciences - Abstract
We tried to image obstructive cholestasis by using a newly developed imaging system to measure the alterations of hepatobiliary function in living mice with their bile ducts ligated. A hepatic imaging window was installed on the upper abdomen soon after the mice underwent ligation of the common bile duct. On the next day, the mice received intravenous injection of rhodamine B isothiocyanate-dextran and carboxyfluorescein diacetate. The later would be transformed into fluorogenic carboxyfluorescein (detected at ~500-550 nm) by hepatocytes and then excreted into bile canaliculi. The images were acquired by multiphoton microscopy. The fluorescence intensities at ~500-550 nm within hepatocytes or sinusoids were measured in time series. In mice with bile duct ligation, bile canaliculi failed to appear during the whole observation period over 100 min following carboxyfluorescein diacetate injection, whereas the fluorescence was retained much longer within sinusoids. Furthermore, the fluorescence intensities in sinusoids were persistently higher than in hepatocytes during the course. Bile duct ligation impedes hepatocytes to excrete carboxyfluorescein into bile canaliculi. The kinetics of fluorescence intensities in hepatocytes and sinusoids indicated there is an active machinery operating backflow of this fluorogenic bile solute from hepatocytes into sinusoids in the liver with obstructive cholestasis. multiphoton microscopy; hepatocyte transporter; fluorescence imaging; common bile duct ligation
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- 2009
45. Forkhead box M1B is a determinant of rat susceptibility to hepatocarcinogenesis and sustains ERK activity in human HCC
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Calvisi, D.F., Pinna, F., Ladu, S., Pellegrino, R., Simile, M.M., Frau, M., De Miglio, M.R., Tomasi, M.L., Sanna, V., Muroni, M.R., Feo, F., and Pascale, R.M.
- Subjects
Hepatoma -- Development and progression ,Hepatoma -- Genetic aspects ,Hepatoma -- Research ,Liver cells -- Genetic aspects ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Peptide regulatory factors -- Physiological aspects ,Peptide regulatory factors -- Research ,Health - Published
- 2009
46. JNK inhibition sensitises hepatocellular carcinoma cells but not normal hepatocytes to the TNF-related apoptosis-inducing ligand
- Author
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Mucha, S.R., Rizzani, A., Gerbes, A.L., Camaj, P., Thasler, W.E., Bruns, C.J., Eichhorst, S.T., Gallmeier, E., Kolligs, F.T., Goke, B., and De Toni, E.N.
- Subjects
Protein kinases -- Physiological aspects ,Protein kinases -- Research ,Hepatoma -- Development and progression ,Hepatoma -- Research ,Tumor necrosis factor -- Physiological aspects ,Ligands (Biochemistry) -- Physiological aspects ,Ligands (Biochemistry) -- Research ,Apoptosis -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Health - Published
- 2009
47. Hepatocyte differentiation of mesenchymal stem cells from human adipose tissue in vitro promotes hepatic integration in vivo
- Author
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Aurich, H., Sgodda, M., Kaltwaber, P., Vetter, M., Weise, A., Liehr, T., Brulport, M., Hengstler, J.G., Dollinger, M.M., Fleig, W.E., and Christ, B.
- Subjects
Liver cells -- Physiological aspects ,Liver cells -- Comparative analysis ,Stem cells -- Comparative analysis ,Adipose tissues -- Physiological aspects ,Adipose tissues -- Comparative analysis ,Liver -- Transplantation ,Liver -- Patient outcomes ,Liver -- Research ,Health - Published
- 2009
48. Knockdown of hepatocyte aquaporin-8 by RNA interference induces defective bile canalicular water transport
- Author
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Larocca, M. Cecilia, Soria, Leandro R., Espelt, M. Victoria, Lehmann, Guillermo L., and Marinelli, Raul A.
- Subjects
Aquaporins -- Physiological aspects ,Biological transport -- Research ,Liver cells -- Physiological aspects ,Liver cells -- Research ,Biological sciences - Abstract
Aquaporin-8 (AQP8) water channels, which are expressed in rat hepatocyte bile canalicular membranes, are involved in water transport during bile formation. Nevertheless, there is no conclusive evidence that AQP8 mediates water secretion into the bile canaliculus. In this study, we directly evaluated whether AQP8 gene silencing by RNA interference inhibits canalicular water secretion in the human hepatocyte-derived cell line, HepG2. By RT-PCR and immunoblotting we found that HepG2 cells express AQP8 and by confocal immunofluorescence microscopy that it is localized intracellularly and on the canalicular membrane, as described in rat hepatocytes. We also verified the expression of AQP8 in normal human liver. Forty-eight hours after transfection of HepG2 cells with RNA duplexes targeting two different regions of human AQP8 molecule, the levels of AQP8 protein specifically decreased by 60-70%. We found that AQP8 knockdown cells showed a significant decline in the canalicular volume of ~70% (P < 0.01), suggesting an impairment in the basal (nonstimulated) canalicular water movement. We also found that the decreased AQP8 expression inhibited the canalicular water transport in response either to an inward osmotic gradient (-65%, P < 0.05) or to the bile secretory agonist dibutyryl cAMP (-80%, P < 0.05). Our data suggest that AQP8 plays a major role in water transport across canalicular membrane of HepG2 cells and support the notion that defective expression of AQP8 causes bile secretory dysfunction in human hepatocytes. HepG2; human liver; bile secretion; dibutyryl cAMP
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- 2009
49. Linoleic acid stimulates gluconeogenesis via [Ca.sup.2+]/PLC, [cPLA.sub.2], and PPAR pathways through GPR40 in primary cultured chicken hepatocytes
- Author
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Suh, Han Na, Huong, Huang Thi, Song, Chang Hun, Lee, Jang Hern, and Han, Ho Jae
- Subjects
Liver cells -- Physiological aspects ,Liver cells -- Research ,Linoleic acids -- Physiological aspects ,Linoleic acids -- Research ,Cell receptors -- Physiological aspects ,Cell receptors -- Reorganization and restructuring ,Gluconeogenesis -- Research ,Company restructuring/company reorganization ,Company organization ,Biological sciences - Abstract
Fatty acids serve vital functions as sources of energy, building materials for cellular structures, and modulators of physiological responses. Therefore, this study examined the effect of linoleic acid on glucose production and its related signal pathways in primary cultured chicken hepatocytes. Linoleic acid (double-unsaturated, long chain) increased glucose production in a dose ([greater than or equal to] [10.sup.-4] M)- and time ([greater than or equal to] 8 h)-dependent manner. Both oleic acid (monounsaturated, long chain) and palmitic acid (saturated, long chain) also increased glucose production, whereas caproic acid (saturated, short chain) tailed to increase glucose production. Linoleic acid increased G protein-coupled receptor 40 (GPR40; also known as free fatty acid receptor-l) protein expression and glucose production that was blocked by GPR40-specific small interfering RNA. Linoleic acid increased intracellular calcium concentration, which was blocked by EGTA (extracellular calcium chelator)/BAPTA-AM (intracellular calcium chelator), U-73122 (phospholipase C inhibitor), nifedipine, or methoxyverapamil (L-type calcium channel blockers). Linoleic acid increased cytosolic phospholipase [A.sub.2] ([cPLA.sub.2]) phosphorylation and the release of [[sup.13]H]-labeled arachidonic acid. Moreover, linoleic acid increased the level of cyclooxygenase-2 (COX-2) protein expression, which stimulated the synthesis of prostaglandin [E.sub.2] ([PGE.sub.2]). The increase in [PGE.sub.2] production subsequently stimulated peroxisome proliferator-activated receptor (PPAR) expression, and MK-886 (PPAR-[alpha] antagonist) and GW-9662 (PPAR-[delta] antagonist) inhibited glucose-6-phosphatase and phosphoenolpyruvate carboxykinase. In addition, linoleic acid-induced glucose production was blocked by inhibition of extracellular and intracellular calcium, [cPLA.sub.2], COX-2, or PPAR pathways. In conclusion, linoleic acid promoted glucose production via [Ca.sup.2+]/PLC, [cPLA.sub.2]/COX-2, and PPAR pathways through GPR40 in primary cultured chicken hepatocytes. phospholipase C; cytosolic phospholipase [A.sub.2] phospholipase A; cyclooxygenase-2; peroxisome proliferator-activated receptors; G protein-coupled receptor 40; free fatty acid; glucose; liver
- Published
- 2008
50. Altered expression and distribution of aquaporin-9 in the liver of rat with obstructive extrahepatic cholestasis
- Author
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Calamita, Giuseppe, Ferri, Domenico, Gena, Patrizia, Carreras, Flavia I., Liquori, Giuseppa E., Portincasa, Piero, Marinelli, Raul A., and Svelto, Maria
- Subjects
Rats as laboratory animals -- Physiological aspects ,Liver cells -- Physiological aspects ,Genes -- Research ,Biological sciences - Abstract
Rat hepatocytes express aquaporin-9 (AQP9), a basolateral channel permeable to water, glycerol, and other small neutral solutes. Although liver AQP9 is known for mediating the uptake of sinusoidal blood glycerol, its relevance in bile secretion physiology and pathophysiology remains elusive. Here, we evaluated whether defective expression of AQP9 is associated to secretory dysfunction of rat hepatocytes following bile duct ligation (BDL). By immunoblotting, 1-day BDL resulted in a slight decrease of AQP9 protein in basolateral membranes and a simultaneous increase of AQP9 in intracellular membranes. This pattern was steadily accentuated in the subsequent days of BDL since at 7 days BDL basolateral membrane AQP9 decreased by 85% whereas intracellular AQP9 increased by 115%. However, the AQP9 immunoreactivity of the total liver membranes from day 7 of BDL rats was reduced by 49% compared with the sham counterpart. Results were confirmed by immunofluorescence and immunogold electron microscopy and consistent with biophysical studies showing considerable decrease of the basolateral membrane water and glycerol permeabilities of cholestatic hepatocytes. The AQP9 mRNA was slightly reduced only at day 7 of BDL, indicating that the dysregulation was mainly occurring at a posttranslational level. The altered expression of liver AQP9 during BDL was not dependent on insulin, a hormone known to negatively regulate AQP9 at a transcriptional level, since insulinemia was unchanged in 7-day BDL rats. Overall, these results suggest that extrahepatic cholestasis leads to downregulation of AQP9 in the hepatocyte basolateral plasma membrane and dysregulated aquaporin channels contribute to bile flow dysfunction of cholestatic hepatocyte. aquaglyceroporin; water channel; bile; bile duct ligation
- Published
- 2008
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