- Email: [email protected]
Caspase-8 Deficiency Ameliorates Hepatic Steatosis, but not Apoptosis in Alcoholic Liver Injury
POSTER PRESENTATIONS Methods: Seven week old female C57BL/6 mice were fed with a LieberDe-Carli diet (EtOH-fed), containing an increasing concentration of ethanol up to 5 vol%, for 15 days, or control diet with an isocaloric amount of maltose (Pair-fed). One half of both groups were treated with 1.5 × 109 A.muc./200 μL PBS six times during the experiment (EtOH-fed + A.muc.; Pair-fed + A.muc.), and the other half obtained an equivalent amount of PBS. Results: Ethanol significantly reduces the abundance of A.muc. in the stool, whereas probiotic treatment with A.muc. restores the number of bacteria. A.muc. treatment significantly ameliorated alcohol induced ALT ( p = <0.01) and liver-body ratio (p = <0.001), indicating an improved progression of ALD. The expression of Tnfα ( p = 0.1392) and Il-1β ( p = 0.0538), two key players in the progression of ALD, was reversed by probiotic treatment. Histological evaluation using a modified brunt score showed significant ( p = <0.05) improvement in regard to liver inflammation and steatosis in A. muc.-treated mice. The observed effects could be explained by restoration of the ethanol damaged gut barrier and therefore reduced systemic LPS levels ( p = <0.05). This finding was contributed by significant thicker mucus layer (p = <0.01, higher number of goblet cells ( p = <0.05) and also increased expression of Claudin 3 ( p = <0.01) in EtOH-fed + A.muc. mice compared to their littermates. Conclusions: Our study indicates a possible role of A.muc. as a therapeutic probiotic in the treatment of ALD. THU-285 ADMINISTRATION OF BIFIDOBACTERIUM SP. LI09 OR BIFIDOBACTERIUM SP. LI10 ATTENUATES ACUTE LIVER DAMAGE INDUCED BY D-GALACTOSAMINE IN RATS D. Fang1,2, D. Shi1,2, L. Lv1,2, W. Wu1,2, F. Guo1,2, L. Li1,2. 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University; 2 Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Hangzhou, China E-mail: [email protected] Background and Aims: Translocation of bacteria or their products can aggravate liver damage. This work investigated the effect of five bifidobacteria from healthy people on acute liver injury in rats by gavages. Methods: Sprague-Dawley rats were given intragastric supplements of Bifidobacterium sp. LI06, Bifidobacterium sp. LI07, Bifidobacterium sp. LI08, Bifidobacterium sp. LI09 or Bifidobacterium sp. LI10 for 7 days. Acute liver injury was induced on the 8th day by an intraperitoneal injection of 1.1 g/kg body weight of D-galactosamine. After 24 hours, samples were collected to determine the plasma levels of cytokines and chemokines, liver function, histology of liver and terminal ileum, composition of the gut microbiome and bacterial translocation. Results: The results indicated that pretreatment with Bifidobacterium sp. LI09 or Bifidobacterium sp. LI10 significantly decreased the plasma level of macrophage colony stimulating factor (M-CSF), macrophage inflammatory protein 1 alpha (MIP-1α) and monocyte chemotactic protein 1 (MCP-1), reduced elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, reduced histological abnormalities of both liver and terminal ileum, resulted in a cecal microbiome which partly returned to normal and decreased bacterial translocation (BT). Pretreatment with Bifidobacterium sp. LI06, Bifidobacterium sp. LI07 or Bifidobacterium sp. LI08 did not demonstrate so significant effects during this process. Conclusions: The excellent characteristics of Bifidobacterium sp. LI09 and Bifidobacterium sp. LI10 enable them to serve as potential probiotics for the prevention or treatment of acute liver injury.
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THU-286 METABOLOMIC ANALYSIS OF THE DYNAMIC CHANGES OF FAECES IN THE ACUTE LIVER FAILURE PIGS E. Chen1,2, Y. Wang1,2, J. Wang1,2, J. Lu1,2, D. Zhu1,2, L. Li1,2. 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University; 2 Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China E-mail: [email protected] Background and Aims: Acute liver failure (ALF) is an intractable disease associated with serious metabolic disorder. Investigating the dynamic changes of faecal metabolites during the development of ALF will reveal the cooperation between the microbiome and the metabolism of mammalian hosts. Therefore, this study characterized the dynamic metabonome of faecal extracted from ALF pigs with ultra performance liquid chromatography-mass spectrometry. Methods: 12 Bama experimental miniature pigs were housed for 14 days for acclimatization, and their food intake were controlled. ALF was induced via intravenous administration of D-galactosamine (1.3 g/kg body weight). Faeces samples were collected at four different given time points: before the administration of D-gal (healthy group), at 12 h (acute liver injury group) and 24 h (acute liver failure group) after its administration, and at death time (death group). Faecal water was extracted by mixed with methanol at a ratio of 5 mL/g. Faecal metabolites were studied with ultra performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS). Metabolic features were then statistically analyzed using partial least squares to latent structurediscriminant analysis (PLS-DA) models to discriminate between healthy, liver injury, liver failure and death states. PLS-DA was also used to identify potential biomarkers which expressed at significantly different amounts. Results: Score plots of pattern recognition analysis distinguished acute liver injury group, acute liver failure group and death group from healthy group. From the result of canonical discriminant analysis, we found that fecal metabonomic data was able to predict the severity of liver failure. Based on the variable of importance in the project (VIP) values and S-plots, we identified four major groups of metabolites, which were considered as potential biomarkers: lysophosphatidylcholines, aromatic amino acids, fatty acids amides and bile acids. The results demonstrate that the potential of UPLC-MS is an efficient and convenient method that can be applied to screen fecal samples and aid in the early diagnosis of acute liver injury and acute liver failure. Conclusions: This study indicated that the UPLC-MS technique is an alternative tool for the metabonomic study, and the metabonomics approach promises to provide an integrative criterion to evaluate the severity degree of liver failure. THU-287 CASPASE-8 DEFICIENCY AMELIORATES HEPATIC STEATOSIS, BUT NOT APOPTOSIS IN ALCOHOLIC LIVER INJURY F. Hao1, F.J. Cubero1, L. Liao1, P. Ramadori1, U. Haas1, D. Lambertz1, N. Gassler2, M. Hoss3, K. Streetz1, J. Reissing1, H.W. Zimmermann1, C. Trautwein1, C. Liedtke1, Y.A. Nevzorova1. 1Department of Medicine III, University Hospital Aachen, Aachen; 2Institute of Pathology, Klinikum Braunschweig, Braunschweig; 3Electron Microscopic Facility, University Hospital Aachen, Aachen, Germany E-mail: [email protected] Background and Aims: Alcoholic liver disease (ALD) is a serious health problem which accounts for about 3.8% of all deaths worldwide. It has been described that ALD is associated with hepatic steatosis and apoptosis. Caspase-8, the apical initiator in death receptor-mediated apoptosis, plays an essential role in acute liver injury and in experimental non-alcoholic steatohepatitis (NASH). However, the physiological relevance of caspase-8 in the pathogenesis of ALD remains unknown.
Journal of Hepatology 2016 vol. 64 | S213–S424
POSTER PRESENTATIONS Methods: The impact of caspase-8 in human ALD and in experimental ethanol-induced apoptosis was investigated in human liver biopsy samples, primary murine hepatocytes and in mice with hepatocytespecific caspase-8 deletion (Casp8Δhepa) fed with ethanol (EtOH) containing Lieber-DeCarli diet for 8 weeks. Results: Increased expression of caspase-8 was detected in liver biopsies from patients with ALD and in livers of wild-type (WT) mice after chronic ethanol feeding. EtOH-fed Casp8Δhepa mice showed significantly attenuated steatosis and hepatic triglycerides content, which were linked to an impaired hepatic intake of free fatty acids (FFA). Surprisingly, lack of caspase-8 in hepatocytes failed to prevent alcoholinduced liver damage and apoptosis, as suggested by similar levels of serum transaminases, TUNEL staining and caspase-3 activation in EtOH-fed Casp8Δhepa and WT mice. Noticeably, the hepatic expression of major extrinsic death receptors and activators (TNFR, TNFα, FasR) was disrupted in Casp8Δhepa animals. However, these effects were compensated by pronounced activation of the intrinsic apoptosis pathway including enhanced cytochrome c release, caspase-9 activation and specific morphological changes in the mitochondria. Finally, in vitro intervention studies using a pan-caspase inhibitor in EtOH-treated primary hepatocytes evidenced that only simultaneous blockage of both intrinsic and extrinsic apoptosis pathways can markedly attenuate alcohol-induced hepatocyte damage. Conclusions: Our results suggest that caspase-8 plays a key role in pathological features of fatty liver steatosis but not ultimately in alcohol-induced apoptosis. Instead, inhibition of caspase-8 during ALD progression may trigger a shift from extrinsic towards intrinsic apoptosis signaling. We conclude that only a broad pharmacological targeting of caspases using pan-caspase inhibitors might be a plausible treatment option for patients with ALD. THU-288 HIGH RISK OF ALCOHOLIC CIRRHOSIS AFTER AN INITIAL ALCOHOL HOSPITAL CONTACT: A POPULATION-BASED STUDY (1998–2014) G. Askgaard1,2, D.A. Leon3, T.A. Gerds4, M.S. Kjær5, T. Deleuran6, J.S. Tolstrup2. 1Department of Hepatology, Copenhagen University Hospital, Rigshospitalet; 2National Institute of Public Health, Copenhagen, Denmark; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; 4University of Copenhagen; 5 Department of Hepatology, Copenhagen University Hospital, Rigshopitalet; 6Aarhus University, Copenhagen, Denmark E-mail: [email protected] Background and Aims: It usually takes 10–20 years of heavy drinking to develop alcoholic cirrhosis. A hospital contact with alcohol problems could therefore represent an opportunity for initiating preventive interventions. We estimated the 15-year risk of alcoholic cirrhosis in patients who had a hospital contact due to alcohol problems. Methods: The study was based on nationwide registries and included all patients in Denmark with a first hospital contact during 1998– 2002 with alcohol problems (alcohol intoxication, harmful alcohol use or alcohol dependence) and free of alcoholic liver disease and other forms of cirrhosis. Follow up for incident alcoholic cirrhosis was conducted until 2014. First, we estimated the risk for alcoholic cirrhosis in the cohort relative to the general Danish population as incidence rate ratios (IRR). Second, using the Aalen-Johansen method, we calculated absolute risks for alcoholic cirrhosis in the cohort taking the competing risk of death into account. Results: The cohort comprised 36,044 people who had a hospital contact with alcohol problems (mean age 43). Of these, 1,406 men and 560 women developed alcoholic cirrhosis after a follow-up of 411,417 person-years. The incidence rate of alcoholic cirrhosis per 10,000 person-years in the cohort versus the general population was 50 versus 4.8 in men and 42 versus 2.3 in women. This corresponded to an Incidence Rate Ratio (cohort versus general population) for alcoholic cirrhosis of 11 (95%CI: 10–12) for men and 18 (95%CI:15–21) for women. Overall, the absolute risk for alcoholic cirrhosis was 5.9%
(95%CI:5.6;6.2) in men and 5.1% (95%CI:4.7;5.6) in women within 15 years. The risk varied by age (highest in those 40–59 years) and initial alcohol diagnosis. Table 1 presents the estimates for men.
Conclusions: People with an initial hospital contact for alcohol problems are at high subsequent risk for alcoholic cirrhosis development. The risk of alcoholic cirrhosis is especially high in patients 40–59 years and is increasing with the severity of the alcohol diagnosis in all ages. THU-289 EXTRACELLULAR VESICLES AND THEIR MICRORNA CARGOS ARE NOVEL BIOMARKERS AND INTERCELLULAR COMMUNICATORS G. Szabo1, B. Saha1, F. Momen-Heravi1, S. Bala1, K. Kodys1. 1Medicine, University of Massachusetts Medical School, Worcester, United States E-mail: [email protected] Background and Aims: Alcohol induces hepatocyte damage and recruitment of inflammatory cells to the liver. There is no reliable biomarker of alcoholic hepatitis. Extracellular vesicles (EVs) found in the circulation carry mRNA, microRNA (miRs) and proteins and can serve as biomarkers. miR-122 is abundantly expressed in hepatocytes and circulating miR-122 was found in liver injury. We hypothesized that EV-associated miRs can serve as biomarkers and modulate intercellular signaling between hepatocytes and immune cells in alcoholic hepatitis. Methods: EVs were isolated from chronic alcohol-fed (5 weeks of Lieber DeCarli diet) or pair-fed mice sera and from serum of patients with alcoholic hepatitis and characterized by western blot, nanoparticle tracking analysis system and miRNA analysis. Results: The total number of circulating EVs was significantly increased in alcohol-fed mice compared to control mice. Exosomes (40–150 nm) represented most of the EVs (∼80%). MicroRNA array of circulating EVs revealed a significant increase of 7 inflammatory miRs including: miR-192, 122, 30a, 744, 1246, 30b and miR-130a in alcoholfed mice compared to controls. The ROC analyses indicated excellent diagnostic value of miR-192, 122, and 30a to identify alcohol-induced liver injury. In patients with acute alcoholic hepatitis, we found a significant increase in the number of circulating EVs compared to normal controls with an increase in miR-192 and miR-30a in their cargo. Serum miR-122 was increased after alcohol binge drinking. In vitro experiments revealed that exosomes derived from ethanoltreated human hepatocytes were taken up by monocytes and transferred mature miR-122 into monocytes. This horizontally transferred miR-122 inhibited hemeoxygenase-1 expression, a target of miR-122 and sensitized monocytes to LPS stimulation to increase production of pro-inflammatory cytokines, TNF-α and IL-1β; all of these effects were inhibited by exosome-mediated delivery of a miR-122 inhibitor in monocytes. Conclusions: Elevated levels of EVs and their miR signature could serve as biomarkers of alcoholic hepatitis. We found a novel EV-
Journal of Hepatology 2016 vol. 64 | S213–S424
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THU-286 METABOLOMIC ANALYSIS OF THE DYNAMIC CHANGES OF FAECES IN THE ACUTE LIVER FAILURE PIGS E. Chen1,2, Y. Wang1,2, J. Wang1,2, J. Lu1,2, D. Zhu1,2, L. Li1,2. 1State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University; 2 Collaborative Innovation Center for Diagnosis and Treatment of Infection Diseases, Zhejiang University, Hangzhou, China E-mail: [email protected] Background and Aims: Acute liver failure (ALF) is an intractable disease associated with serious metabolic disorder. Investigating the dynamic changes of faecal metabolites during the development of ALF will reveal the cooperation between the microbiome and the metabolism of mammalian hosts. Therefore, this study characterized the dynamic metabonome of faecal extracted from ALF pigs with ultra performance liquid chromatography-mass spectrometry. Methods: 12 Bama experimental miniature pigs were housed for 14 days for acclimatization, and their food intake were controlled. ALF was induced via intravenous administration of D-galactosamine (1.3 g/kg body weight). Faeces samples were collected at four different given time points: before the administration of D-gal (healthy group), at 12 h (acute liver injury group) and 24 h (acute liver failure group) after its administration, and at death time (death group). Faecal water was extracted by mixed with methanol at a ratio of 5 mL/g. Faecal metabolites were studied with ultra performance liquid chromatography coupled to quadrupole-time-of-flight mass spectrometry (UPLC/Q-TOF MS). Metabolic features were then statistically analyzed using partial least squares to latent structurediscriminant analysis (PLS-DA) models to discriminate between healthy, liver injury, liver failure and death states. PLS-DA was also used to identify potential biomarkers which expressed at significantly different amounts. Results: Score plots of pattern recognition analysis distinguished acute liver injury group, acute liver failure group and death group from healthy group. From the result of canonical discriminant analysis, we found that fecal metabonomic data was able to predict the severity of liver failure. Based on the variable of importance in the project (VIP) values and S-plots, we identified four major groups of metabolites, which were considered as potential biomarkers: lysophosphatidylcholines, aromatic amino acids, fatty acids amides and bile acids. The results demonstrate that the potential of UPLC-MS is an efficient and convenient method that can be applied to screen fecal samples and aid in the early diagnosis of acute liver injury and acute liver failure. Conclusions: This study indicated that the UPLC-MS technique is an alternative tool for the metabonomic study, and the metabonomics approach promises to provide an integrative criterion to evaluate the severity degree of liver failure. THU-287 CASPASE-8 DEFICIENCY AMELIORATES HEPATIC STEATOSIS, BUT NOT APOPTOSIS IN ALCOHOLIC LIVER INJURY F. Hao1, F.J. Cubero1, L. Liao1, P. Ramadori1, U. Haas1, D. Lambertz1, N. Gassler2, M. Hoss3, K. Streetz1, J. Reissing1, H.W. Zimmermann1, C. Trautwein1, C. Liedtke1, Y.A. Nevzorova1. 1Department of Medicine III, University Hospital Aachen, Aachen; 2Institute of Pathology, Klinikum Braunschweig, Braunschweig; 3Electron Microscopic Facility, University Hospital Aachen, Aachen, Germany E-mail: [email protected] Background and Aims: Alcoholic liver disease (ALD) is a serious health problem which accounts for about 3.8% of all deaths worldwide. It has been described that ALD is associated with hepatic steatosis and apoptosis. Caspase-8, the apical initiator in death receptor-mediated apoptosis, plays an essential role in acute liver injury and in experimental non-alcoholic steatohepatitis (NASH). However, the physiological relevance of caspase-8 in the pathogenesis of ALD remains unknown.
Journal of Hepatology 2016 vol. 64 | S213–S424
POSTER PRESENTATIONS Methods: The impact of caspase-8 in human ALD and in experimental ethanol-induced apoptosis was investigated in human liver biopsy samples, primary murine hepatocytes and in mice with hepatocytespecific caspase-8 deletion (Casp8Δhepa) fed with ethanol (EtOH) containing Lieber-DeCarli diet for 8 weeks. Results: Increased expression of caspase-8 was detected in liver biopsies from patients with ALD and in livers of wild-type (WT) mice after chronic ethanol feeding. EtOH-fed Casp8Δhepa mice showed significantly attenuated steatosis and hepatic triglycerides content, which were linked to an impaired hepatic intake of free fatty acids (FFA). Surprisingly, lack of caspase-8 in hepatocytes failed to prevent alcoholinduced liver damage and apoptosis, as suggested by similar levels of serum transaminases, TUNEL staining and caspase-3 activation in EtOH-fed Casp8Δhepa and WT mice. Noticeably, the hepatic expression of major extrinsic death receptors and activators (TNFR, TNFα, FasR) was disrupted in Casp8Δhepa animals. However, these effects were compensated by pronounced activation of the intrinsic apoptosis pathway including enhanced cytochrome c release, caspase-9 activation and specific morphological changes in the mitochondria. Finally, in vitro intervention studies using a pan-caspase inhibitor in EtOH-treated primary hepatocytes evidenced that only simultaneous blockage of both intrinsic and extrinsic apoptosis pathways can markedly attenuate alcohol-induced hepatocyte damage. Conclusions: Our results suggest that caspase-8 plays a key role in pathological features of fatty liver steatosis but not ultimately in alcohol-induced apoptosis. Instead, inhibition of caspase-8 during ALD progression may trigger a shift from extrinsic towards intrinsic apoptosis signaling. We conclude that only a broad pharmacological targeting of caspases using pan-caspase inhibitors might be a plausible treatment option for patients with ALD. THU-288 HIGH RISK OF ALCOHOLIC CIRRHOSIS AFTER AN INITIAL ALCOHOL HOSPITAL CONTACT: A POPULATION-BASED STUDY (1998–2014) G. Askgaard1,2, D.A. Leon3, T.A. Gerds4, M.S. Kjær5, T. Deleuran6, J.S. Tolstrup2. 1Department of Hepatology, Copenhagen University Hospital, Rigshospitalet; 2National Institute of Public Health, Copenhagen, Denmark; 3London School of Hygiene and Tropical Medicine, London, United Kingdom; 4University of Copenhagen; 5 Department of Hepatology, Copenhagen University Hospital, Rigshopitalet; 6Aarhus University, Copenhagen, Denmark E-mail: [email protected] Background and Aims: It usually takes 10–20 years of heavy drinking to develop alcoholic cirrhosis. A hospital contact with alcohol problems could therefore represent an opportunity for initiating preventive interventions. We estimated the 15-year risk of alcoholic cirrhosis in patients who had a hospital contact due to alcohol problems. Methods: The study was based on nationwide registries and included all patients in Denmark with a first hospital contact during 1998– 2002 with alcohol problems (alcohol intoxication, harmful alcohol use or alcohol dependence) and free of alcoholic liver disease and other forms of cirrhosis. Follow up for incident alcoholic cirrhosis was conducted until 2014. First, we estimated the risk for alcoholic cirrhosis in the cohort relative to the general Danish population as incidence rate ratios (IRR). Second, using the Aalen-Johansen method, we calculated absolute risks for alcoholic cirrhosis in the cohort taking the competing risk of death into account. Results: The cohort comprised 36,044 people who had a hospital contact with alcohol problems (mean age 43). Of these, 1,406 men and 560 women developed alcoholic cirrhosis after a follow-up of 411,417 person-years. The incidence rate of alcoholic cirrhosis per 10,000 person-years in the cohort versus the general population was 50 versus 4.8 in men and 42 versus 2.3 in women. This corresponded to an Incidence Rate Ratio (cohort versus general population) for alcoholic cirrhosis of 11 (95%CI: 10–12) for men and 18 (95%CI:15–21) for women. Overall, the absolute risk for alcoholic cirrhosis was 5.9%
(95%CI:5.6;6.2) in men and 5.1% (95%CI:4.7;5.6) in women within 15 years. The risk varied by age (highest in those 40–59 years) and initial alcohol diagnosis. Table 1 presents the estimates for men.
Conclusions: People with an initial hospital contact for alcohol problems are at high subsequent risk for alcoholic cirrhosis development. The risk of alcoholic cirrhosis is especially high in patients 40–59 years and is increasing with the severity of the alcohol diagnosis in all ages. THU-289 EXTRACELLULAR VESICLES AND THEIR MICRORNA CARGOS ARE NOVEL BIOMARKERS AND INTERCELLULAR COMMUNICATORS G. Szabo1, B. Saha1, F. Momen-Heravi1, S. Bala1, K. Kodys1. 1Medicine, University of Massachusetts Medical School, Worcester, United States E-mail: [email protected] Background and Aims: Alcohol induces hepatocyte damage and recruitment of inflammatory cells to the liver. There is no reliable biomarker of alcoholic hepatitis. Extracellular vesicles (EVs) found in the circulation carry mRNA, microRNA (miRs) and proteins and can serve as biomarkers. miR-122 is abundantly expressed in hepatocytes and circulating miR-122 was found in liver injury. We hypothesized that EV-associated miRs can serve as biomarkers and modulate intercellular signaling between hepatocytes and immune cells in alcoholic hepatitis. Methods: EVs were isolated from chronic alcohol-fed (5 weeks of Lieber DeCarli diet) or pair-fed mice sera and from serum of patients with alcoholic hepatitis and characterized by western blot, nanoparticle tracking analysis system and miRNA analysis. Results: The total number of circulating EVs was significantly increased in alcohol-fed mice compared to control mice. Exosomes (40–150 nm) represented most of the EVs (∼80%). MicroRNA array of circulating EVs revealed a significant increase of 7 inflammatory miRs including: miR-192, 122, 30a, 744, 1246, 30b and miR-130a in alcoholfed mice compared to controls. The ROC analyses indicated excellent diagnostic value of miR-192, 122, and 30a to identify alcohol-induced liver injury. In patients with acute alcoholic hepatitis, we found a significant increase in the number of circulating EVs compared to normal controls with an increase in miR-192 and miR-30a in their cargo. Serum miR-122 was increased after alcohol binge drinking. In vitro experiments revealed that exosomes derived from ethanoltreated human hepatocytes were taken up by monocytes and transferred mature miR-122 into monocytes. This horizontally transferred miR-122 inhibited hemeoxygenase-1 expression, a target of miR-122 and sensitized monocytes to LPS stimulation to increase production of pro-inflammatory cytokines, TNF-α and IL-1β; all of these effects were inhibited by exosome-mediated delivery of a miR-122 inhibitor in monocytes. Conclusions: Elevated levels of EVs and their miR signature could serve as biomarkers of alcoholic hepatitis. We found a novel EV-
Journal of Hepatology 2016 vol. 64 | S213–S424
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