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CD8 T cells regulate liver injury in obesity-related nonalcoholic fatty liver disease.
Breuer DA, Pacheco MC, Washington MK, Montgomery SA, Hasty AH, Kennedy AJ
(2020) Am J Physiol Gastrointest Liver Physiol 318: G211-G224
MeSH Terms: Animals, CD8-Positive T-Lymphocytes, Hepatic Stellate Cells, Hepatitis, Humans, Hyperlipidemias, Interleukin-10, Liver, Male, Mice, Mice, Inbred C57BL, Mice, Obese, Non-alcoholic Fatty Liver Disease, Obesity, Receptors, LDL
Show Abstract · Added March 3, 2020
Nonalcoholic steatohepatitis (NASH) has increased in Western countries due to the prevalence of obesity. Current interests are aimed at identifying the type and function of immune cells that infiltrate the liver and key factors responsible for mediating their recruitment and activation in NASH. We investigated the function and phenotype of CD8 T cells under obese and nonobese NASH conditions. We found an elevation in CD8 staining in livers from obese human subjects with NASH and cirrhosis that positively correlated with α-smooth muscle actin, a marker of hepatic stellate cell (HSC) activation. CD8 T cells were elevated 3.5-fold in the livers of obese and hyperlipidemic NASH mice compared with obese hepatic steatosis mice. Isolated hepatic CD8 T cells from these mice expressed a cytotoxic IL-10-expressing phenotype, and depletion of CD8 T cells led to significant reductions in hepatic inflammation, HSC activation, and macrophage accumulation. Furthermore, hepatic CD8 T cells from obese and hyperlipidemic NASH mice activated HSCs in vitro and in vivo. Interestingly, in the lean NASH mouse model, depletion and knockdown of CD8 T cells did not impact liver inflammation or HSC activation. We demonstrated that under obese/hyperlipidemia conditions, CD8 T cell are key regulators of the progression of NASH, while under nonobese conditions they play a minimal role in driving the disease. Thus, therapies targeting CD8 T cells may be a novel approach for treatment of obesity-associated NASH. Our study demonstrates that CD8 T cells are the primary hepatic T cell population, are elevated in obese models of NASH, and directly activate hepatic stellate cells. In contrast, we find CD8 T cells from lean NASH models do not regulate NASH-associated inflammation or stellate cell activation. Thus, for the first time to our knowledge, we demonstrate that hepatic CD8 T cells are key players in obesity-associated NASH.
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15 MeSH Terms
The liver.
Trefts E, Gannon M, Wasserman DH
(2017) Curr Biol 27: R1147-R1151
MeSH Terms: Amino Acids, Animals, Biological Transport, Energy Metabolism, Glucose, Glycogen, Hepatic Stellate Cells, Humans, Kupffer Cells, Lipid Metabolism, Liver, Obesity, Proteins
Show Abstract · Added March 26, 2019
The liver is a critical hub for numerous physiological processes. These include macronutrient metabolism, blood volume regulation, immune system support, endocrine control of growth signaling pathways, lipid and cholesterol homeostasis, and the breakdown of xenobiotic compounds, including many current drugs. Processing, partitioning, and metabolism of macronutrients provide the energy needed to drive the aforementioned processes and are therefore among the liver's most critical functions. Moreover, the liver's capacities to store glucose in the form of glycogen, with feeding, and assemble glucose via the gluconeogenic pathway, in response to fasting, are critical. The liver oxidizes lipids, but can also package excess lipid for secretion to and storage in other tissues, such as adipose. Finally, the liver is a major handler of protein and amino acid metabolism as it is responsible for the majority of proteins secreted in the blood (whether based on mass or range of unique proteins), the processing of amino acids for energy, and disposal of nitrogenous waste from protein degradation in the form of urea metabolism. Over the course of evolution this array of hepatic functions has been consolidated in a single organ, the liver, which is conserved in all vertebrates. Developmentally, this organ arises as a result of a complex differentiation program that is initiated by exogenous signal gradients, cellular localization cues, and an intricate hierarchy of transcription factors. These processes that are fully developed in the mature liver are imperative for life. Liver failure from any number of sources (e.g. viral infection, overnutrition, or oncologic burden) is a global health problem. The goal of this primer is to concisely summarize hepatic functions with respect to macronutrient metabolism. Introducing concepts critical to liver development, organization, and physiology sets the stage for these functions and serves to orient the reader. It is important to emphasize that insight into hepatic pathologies and potential therapeutic avenues to treat these conditions requires an understanding of the development and physiology of specialized hepatic functions.
Copyright © 2017 Elsevier Ltd. All rights reserved.
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MeSH Terms
Reactive gamma-ketoaldehydes as novel activators of hepatic stellate cells in vitro.
Longato L, Andreola F, Davies SS, Roberts JL, Fusai G, Pinzani M, Moore K, Rombouts K
(2017) Free Radic Biol Med 102: 162-173
MeSH Terms: Aldehydes, Apoptosis, Autophagy, Cell Proliferation, Hepatic Stellate Cells, Humans, Lipid Peroxidation, Liver, Liver Cirrhosis, NF-kappa B, Oxidative Stress, Prostaglandins E, Reactive Oxygen Species
Show Abstract · Added July 17, 2019
AIMS - Products of lipid oxidation, such as 4-hydroxynonenal (4-HNE), are key activators of hepatic stellate cells (HSC) to a pro-fibrogenic phenotype. Isolevuglandins (IsoLG) are a family of acyclic γ-ketoaldehydes formed through oxidation of arachidonic acid or as by-products of the cyclooxygenase pathway. IsoLGs are highly reactive aldehydes which are efficient at forming protein adducts and cross-links at concentrations 100-fold lower than 4-hydroxynonenal. Since the contribution of IsoLGs to liver injury has not been studied, we synthesized 15-E-IsoLG and used it to investigate whether IsoLG could induce activation of HSC.
RESULTS - Primary human HSC were exposed to 15-E-IsoLG for up to 48h. Exposure to 5μM 15-E-IsoLG in HSCs promoted cytotoxicity and apoptosis. At non-cytotoxic doses (50 pM-500nM) 15-E-IsoLG promoted HSC activation, indicated by increased expression of α-SMA, sustained activation of ERK and JNK signaling pathways, and increased mRNA and/or protein expression of cytokines and chemokines, which was blocked by inhibitors of JNK and NF-kB. In addition, IsoLG promoted formation of reactive oxygen species, and induced an early activation of ER stress, followed by autophagy. Inhibition of autophagy partially reduced the pro-inflammatory effects of IsoLG, suggesting that it might serve as a cytoprotective response.
INNOVATION - This study is the first to describe the biological effects of IsoLG in primary HSC, the main drivers of hepatic fibrosis.
CONCLUSIONS - IsoLGs represent a newly identified class of activators of HSC in vitro, which are biologically active at concentrations as low as 500 pM, and are particularly effective at promoting a pro-inflammatory response and autophagy.
Copyright © 2016. Published by Elsevier Inc.
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Regulation of the activity and expression of aryl hydrocarbon receptor by ethanol in mouse hepatic stellate cells.
Zhang HF, Lin XH, Yang H, Zhou LC, Guo YL, Barnett JV, Guo ZM
(2012) Alcohol Clin Exp Res 36: 1873-81
MeSH Terms: Animals, Cell Line, Transformed, Cells, Cultured, Ethanol, Gene Expression Regulation, Hepatic Stellate Cells, Mice, Mice, Transgenic, Receptors, Aryl Hydrocarbon
Show Abstract · Added February 21, 2016
BACKGROUND - During the course of alcohol-induced liver damage, hepatic stellate cells are transformed into proliferative, fibrogenic, and contractile myofibroblasts. Aryl hydrocarbon receptor (AhR) is a transcription factor that controls the expression of genes involved in the metabolism of xenobiotics, inflammation, cell proliferation, and death.
METHODS - Immortal mouse hepatic stellate cells (MHSCs) were isolated from transgenic mice that expressed a thermolabile SV40 tumor antigen. Quantitative real-time reverse transcription polymerase chain reaction assays, Western blot analysis, promoter activity assays, and chromatin immunoprecipitation analyses were performed for studying the effect of ethanol (EtOH) on AhR expression and transcriptional activity.
RESULTS - Treatment of MHSCs with 50 to 200 mM EtOH for 6 hours induced AhR nuclear translocation, enhanced the promoter activity of cytochrome P450 (CYP) 1A1, increased the amount of AhR bound to the promoter of CYP1A1 and 1B1, and up-regulated the mRNA expression of these AhR target genes in a dose-dependent manner. In contrast, EtOH exposure down-regulated AhR mRNA and protein expression. Similarly, benzo(a)pyrene (BaP) at 10 nM reduced AhR and increased CYP1A1 and 1B1 mRNAs. Pretreatment of MHSCs with 50 mM EtOH for 7 days diminished the capacity of MHSCs to express CYP1A1 and 1B1 induced by a 200 mM EtOH challenge, or by 10 nM BaP. However, the up-regulatory effect of EtOH on solute carrier family 16, member 6 (SLC16a6) was unaffected by EtOH pretreatment. Similar to EtOH, dimethyl sulfoxide (DMSO) at concentrations of 50 to 100 mM down-regulated AhR and up-regulated CYP1A1 mRNA expression in a dose-dependent manner.
CONCLUSIONS - These data, for the first time, demonstrate that EtOH activates MHSC AhR and down-regulates its expression. Chronic EtOH pretreatment lowers the availability of AhR, and specifically diminishes the inducibility of CYP genes. The effect on AhR appears to not be an EtOH-specific response, as DMSO alone (and possibly other organic solvents) was also able to activate AhR.
Copyright © 2012 by the Research Society on Alcoholism.
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9 MeSH Terms
Prediction of hepatocellular carcinoma development by plasma ADAMTS13 in chronic hepatitis B and C.
Ikeda H, Tateishi R, Enooku K, Yoshida H, Nakagawa H, Masuzaki R, Kondo Y, Goto T, Shiina S, Kume Y, Tomiya T, Inoue Y, Nishikawa T, Ohtomo N, Tanoue Y, Ono T, Koike K, Yatomi Y
(2011) Cancer Epidemiol Biomarkers Prev 20: 2204-11
MeSH Terms: ADAM Proteins, ADAMTS13 Protein, Aged, Alanine Transaminase, Aspartate Aminotransferases, Biomarkers, Tumor, Blood Proteins, Carcinoma, Hepatocellular, Case-Control Studies, Enzyme-Linked Immunosorbent Assay, Female, Follow-Up Studies, Hepacivirus, Hepatic Stellate Cells, Hepatitis B virus, Hepatitis B, Chronic, Hepatitis C, Chronic, Humans, Liver Neoplasms, Male, Middle Aged, Neoplasm Recurrence, Local, Prognosis
Show Abstract · Added May 2, 2014
BACKGROUND - Chronic liver injury evokes a wound healing response, promoting fibrosis and finally hepatocellular carcinoma (HCC), in which hepatic stellate cells play an important role. Although a blood marker of hepatic stellate cells is not known, those cells importantly contribute to the regulation of plasma a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) activity, a defect of which causes thrombotic thrombocytopenic purpura.
METHODS - Plasma ADAMTS13 was evaluated in chronic hepatitis B or C patients with or without HCC.
RESULTS - Plasma ADAMTS13 activity significantly correlated with serum aspartate aminotransferase and alanine aminotransferase, liver stiffness value, and aspartate aminotransferase-to-platelet ratio index, irrespective of the presence of HCC, suggesting that it may reflect hepatocellular damage and subsequent wound healing and fibrosis as a result of hepatic stellate cell action. During the three-year follow-up period for patients without HCC, it developed in 10 among 81 patients. Plasma ADAMTS13 activity was significantly higher in patients with HCC development than in those without and was a significant risk for HCC development by univariate and multivariate analyses. Furthermore, during the one-year follow-up period for patients with HCC treated with radiofrequency ablation, HCC recurred in 55 among 107 patients. Plasma ADAMTS13 activity or antigen level was significantly higher in patients with HCC recurrence than in those without and was retained as a significant risk for HCC recurrence by multivariate analysis.
CONCLUSIONS - Higher plasma ADAMTS13 activity and antigen level was a risk of HCC development in chronic liver disease.
IMPACT - Plasma ADAMTS13 as a potential marker of hepatic stellate cells may be useful in the prediction of hepatocarcinogenesis.
©2011 AACR
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23 MeSH Terms
Genetic labeling does not detect epithelial-to-mesenchymal transition of cholangiocytes in liver fibrosis in mice.
Scholten D, Osterreicher CH, Scholten A, Iwaisako K, Gu G, Brenner DA, Kisseleva T
(2010) Gastroenterology 139: 987-98
MeSH Terms: Animals, Bile Ducts, Biomarkers, Calcium-Binding Proteins, Carbon Tetrachloride, Cell Lineage, Cell Transdifferentiation, Chemical and Drug Induced Liver Injury, Collagen Type II, Crosses, Genetic, Disease Models, Animal, Epithelial Cells, Fibroblasts, Genes, Reporter, Glial Fibrillary Acidic Protein, Hepatic Stellate Cells, Immunohistochemistry, Keratin-19, Ligation, Liver, Liver Cirrhosis, Liver Regeneration, Luminescent Proteins, Mice, Mice, Transgenic, Promoter Regions, Genetic, Proteins, RNA, Untranslated, S100 Calcium-Binding Protein A4, S100 Proteins
Show Abstract · Added December 4, 2012
BACKGROUND & AIMS - Chronic injury changes the fate of certain cellular populations, inducing epithelial cells to generate fibroblasts by epithelial-to-mesenchymal transition (EMT) and mesenchymal cells to generate epithelial cells by mesenchymal-to-epithelial transition (MET). Although contribution of EMT/MET to embryogenesis, renal fibrosis, and lung fibrosis is well documented, role of EMT/MET in liver fibrosis is unclear. We determined whether cytokeratin-19 positive (K19(+)) cholangiocytes give rise to myofibroblasts (EMT) and/or whether glial fibrillary acidic protein positive (GFAP(+)) hepatic stellate cells (HSCs) can express epithelial markers (MET) in response to experimental liver injury.
METHODS - EMT was studied with Cre-loxP system to map cell fate of K19(+) cholangiocytes in K19(YFP) or fibroblast-specific protein-1 (FSP-1)(YFP) mice, generated by crossing tamoxifen-inducible K19(CreERT) mice or FSP-1(Cre) mice with Rosa26(f/f-YFP) mice. MET of GFAP(+) HSCs was studied in GFAP(GFP) mice. Mice were subjected to bile duct ligation or CCl(4)-liver injury, and livers were analyzed for expression of mesodermal and epithelial markers.
RESULTS - On Cre-loxP recombination, >40% of genetically labeled K19(+) cholangiocytes expressed yellow fluorescent protein (YFP). All mice developed liver fibrosis. However, specific immunostaining of K19(YFP) cholangiocytes showed no expression of EMT markers alpha-smooth muscle actin, desmin, or FSP-1. Moreover, cells genetically labeled by FSP-1(YFP) expression did not coexpress cholangiocyte markers K19 or E-cadherin. Genetically labeled GFAP(GFP) HSCs did not express epithelial or liver progenitor markers in response to liver injury.
CONCLUSION - EMT of cholangiocytes identified by genetic labeling does not contribute to hepatic fibrosis in mice. Likewise, GFAP(Cre)-labeled HSCs showed no coexpression of epithelial markers, providing no evidence for MET in HSCs in response to fibrogenic liver injury.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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30 MeSH Terms