Effects Of Liver Injury Research Articles

Augmenter of liver regeneration (ALR) exhibits a dual signaling impact on hepatic acute-phase response

The acute-phase response (APR) is an inflammatory process triggered mainly by IL-6 in response to neoplasm, tissue injury, infection or inflammation. Signaling of IL-6 is transduced by activating STAT3 which rapidly results in production of acute-phase proteins (APPs) such as fibrinogen β (FGB) and haptoglobin (HP). Augmenter of liver regeneration (ALR), a hepatotrophic factor supporting liver regeneration, was reported to be upregulated after liver damage. In this study we analyzed the role of ALR for IL-6 signaling and APR. Thus, we investigated the expression and release of APPs in human liver cells under conditions of increased exogenous or endogenous ALR. HepG2 cells and ALR-reexpressing HepG2 cells were treated with IL-6 in the presence or absence of exogenous ALR for different time points. The mRNA expression and release of both FGB and HP were measured by RT-PCR and ELISA. We found that exogenously applied ALR attenuated the IL-6-induced mRNA expression and protein secretion of both FGB and HP. In contrast, IL-6 stimulation in HepG2 cells which re-express ALR, revealed elevated APR shown by increased mRNA expression and secretion of FGB and HP. Furthermore, we found that ALR-mediated regulation of IL-6-induced APP production is accompanied by altered STAT3 activity. While exogenous ALR reduced the IL-6-induced phosphorylation of STAT3, endogenous ALR enhanced STAT3 activity in liver cells. In conclusion, ALR, dependent on its localization, changes APR at least in part, by modifying STAT3 activation. This study shows a dual signaling of ALR and suggests that ALR is pivotal for the regulation of APR, a crucial event in liver injury and regeneration.

Solithromycin: A novel ketolide antibiotic.

The pharmacology, pharmacokinetics, pharmacodynamics, antimicrobial activity, clinical safety, and current regulatory status of solithromycin are reviewed. Solithromycin is a novel ketolide antibiotic developed for the treatment of community-acquired bacterial pneumonia (CABP). Its pharmacologic, pharmacokinetic, and pharmacodynamic properties provide activity against a broad range of intracellular organisms, including retained activity against pathogens displaying various mechanisms of macrolide resistance. Phase III clinical trials of solithromycin demonstrated noninferiority of both oral and i.v.-to-oral regimens of 5-7 days' duration compared with moxifloxacin for patients with moderately severe CABP. Nearly one third of patients receiving i.v. solithromycin experienced infusion-site reactions. Although no liver-related adverse events were reported in patients receiving oral solithromycin, more patients receiving i.v.-to-oral solithromycin experienced asymptomatic, transient transaminitis, with alanine transaminase levels of >3 to >5 times the upper limit, compared with those treated with moxifloxacin. These results led the Food and Drug Administration to conclude that the solithromycin new drug application was not approvable as filed, adding that the risk of hepatotoxicity had not yet been adequately characterized. The agency further recommended a comparative study of patients with CABP to include approximately 9,000 patients exposed to solithromycin in order to exclude drug-induced liver injury events occurring at a rate of 1 in 3,000 with 95% probability. Solithromycin is a novel ketolide antibiotic with activity against a broad spectrum of intracellular organisms, including those displaying macrolide resistance. While demonstrating noninferiority to a current first-line agent in the treatment of CABP, concerns for drug-induced liver injury and infusion-site reactions have placed its regulatory future in doubt.

Multiple Beneficial effects Associated with Coffee Consumption on Human Liver

Coffee is widely consumed beverage in the world. Incidence of chronic liver disease decreases with intake of coffee.The main objective of this study is to elucidate the hepatoprotective as well as chemo protective effect of coffee consumption in relation to previous published data. Prospective cohort studies based on relationship between coffee intake and ultimate effects on liver cancer have drawn various conclusions. Coffee’s beneficial effects in various disease states have been demonstrated in variety of studies. Studies have provided data regarding effects of coffee in hot as well as in cold state. Level of blood cholesterol, following filtration, is affected by the coffee components. Among the components of coffee, caffeine played the significant role in reducing the level of ALT in coffee consumers as compared with non-coffee consumers. Coffee intake is associated with cardiovascular events and hypertension risks. However, intake of coffee has been found to be inversely related to the level of serum enzymes like gamma-glutamyltransferase, and alanine aminotransferase when studies relating to coffee effect on liver were performed in different countries. Moreover, the data based on epidemiological analysis, clearly suggested that liver cirrhosis had inverse relationship with coffee consumption; however, the results obtained were not sufficient to demonstrate that coffee may have hepatoprotective effect in liver injury. There is emerging evidence revealing that consumption of coffee has been associated with reduction of risks of various types of cancers. The emerging data on coffee consumption has revealed that it has beneficial effects in colorectal, pancreatic, and pharyngeal as well as in liver cancer. A systematic review was performed regarding association of coffee consumption and effect of coffee intake on liver diseases like hepatocellular carcinoma (HCC), viral hepatitis, cirrhosis and nonalcoholic fatty liver disease (NAFLD). Coffee consumption, in dose dependent manner, was found to improve the level of serum gamma-glutamyltransferase, alanine aminotransferase and aspartate aminotransferase in individuals which were found to be at risk of liver diseases. Anticancer effect of coffee on liver is achieved by induction as well as inhibition of specific enzymes. The patients with history of chronic liver disease who consume coffee, were reported to be at a reduced risk of liver to be cirrhotic, and a decreased mortality rate was observed in cirrhosis patients, as well as a decreased rate of development of Hepatocellular carcinoma was observed. In individuals with history of chronic hepatitis C, coffee intake was found to be associated with enhanced virologic reaction to antiviral drug therapy. Furthermore, coffee intake was reported to be inversely associated with the severeness of steatohepatitis in individuals with non-alcoholic fatty liver disorder. Therefore, in patients with chronic liver disease, coffee consumption on daily basis should be persuaded.

Roles of defective ALDH2 polymorphism on liver protection and cancer development.

Because serum transaminases elevate alcohol dose dependently as a consequence of liver injury, they serve as useful biological markers of excessive drinking. However, these markers are inadequate in individuals with a defective allele of the aldehyde dehydrogenase 2 gene, ALDH2*2, because they show a different correlation with the amount of ethanol. For example, the serum alanine aminotransferase (ALT) level could become even lower than the baseline after alcohol intake in ALDH2*2 carriers. In fact, multiple studies suggest that ALDH2*2 is a hepato-protective factor in healthy individuals. Importantly, excessive drinking is particularly dangerous in carriers of ALDH2*2 because the risk of alcohol-related cancer is much higher than that for ALDH2*1/*1 carriers. Without recognizing the genotype interaction on serum transaminase, the opportunity to warn people about potential cancer risks is missed owing to incorrect interpretation. This is particularly important in East Asian countries where approximately half of the population carries the ALDH2*2 allele. To date, the mechanism of liver protection from ethanol load in individuals with ALDH2*2 has not been fully elucidated. However, some reasonable mechanisms have been suggested by experimental studies, including remodelling of detoxifying systems. Further studies to uncover the whole mechanism are anticipated.

Risk of liver injury after α-glucosidase inhibitor therapy in advanced chronic kidney disease patients.

Although α-glucosidase inhibitors (AGIs) are commonly used for controlling postprandial blood glucose, AGIs-induced liver injuries have been reported. However, the relationship between AGIs and liver injuries in advanced chronic kidney disease (CKD) patients remains unexplored. In this nationwide case-control study, we recruited 1765 advanced diabetic CKD patients, who received AGIs therapy from January 1, 2000 to December 31, 2010 as the study sample and 5295 matched controls. Recent and former AGIs users were defined as patients who received the AGIs prescription for 30–60 d and 30–210 d before the event of liver injury. The risk of AGIs-induced liver injury was examined using time-dependent Cox proportional hazards model. Liver injury occurred in 3.9% of patients in the study group and 3.3% of patients in the control group. AGIs use did not increase the risk of liver injury in advanced CKD patients (P = 0.19). The stratified analysis indicated no increased risk of liver injury in all AGIs-using subgroups (all P > 0.05). The available evidence supports extending the use of AGIs without increasing the risk of liver injury in patients with advanced CKD. Additional randomized controlled trials are warranted to confirm our results.

The Chinese medicine Sini-San inhibits HBx-induced migration and invasiveness of human hepatocellular carcinoma cells.

BackgroundSini-San (SNS) is a formulation of four Traditional Chinese Drugs that exhibits beneficial therapeutic effects in liver injury and hepatitis. However, there are no reports describing its effects on the hepatitis B X-protein (HBx)-induced invasion and metastasis in hepatoma cells, and the detailed molecular mechanisms of its actions are still unclear.MethodsIn this study, we investigated the mechanisms underlying SNS-mediated inhibition of HBx-induced cell invasion and the inhibition of secreted and cytosolic MMP-9 production, using gelatin zymography and Western blot analysis in a human hepatoma cell line (HepG2). Relative luciferase activity was assessed for MMP-9, NF-κB, or AP-1 reporter plasmid-transfected cells.ResultsSNS suppressed MMP-9 transcription by inhibiting activator protein (AP)-1 and nuclear factor-κ B (NF-κB) activity. SNS suppressed HBx-induced AP-1 activity through inhibition of phosphorylation in the extracellular signal-related kinase (ERK) and c-Jun N-terminal kinase (JNK) signaling pathways. SNS also suppressed HBx-induced inhibition of NF-κB nuclear translocation through IκB and suppressed HBx-induced activation of ERK/phosphatidylinositol 3-kinase/Akt upstream of NF-κB and AP-1.ConclusionsSNS suppresses the invasiveness and metastatic potential of hepatocellular carcinoma cells by inhibiting multiple signal transduction pathways.

Alcoholic Liver Disease and Alcohol in Non-Alcoholic Liver Disease: Does it Matter?

Alcoholic Liver Disease (ALD) is still a major problem in Western and Asian countries. The long-term impact of ALD might further lead to liver disease complications, such as liver cirrhosis and liver cancer. The safe limit amount of alcohol might be different between Western and Asian countries as the genetic factor might also become an important role in the liver disease progression. It is well-known that alcohol consumption would have synergistic liver injury effect together with chronic viral hepatitis infection. However, in non-alcoholic fatty liver disease (NAFLD), mild to moderate alcohol consumption might have a beneficial effect as it might protect the liver. Further studies will be needed to confirm the beneficial effect of mild to moderate alcohol consumption for protecting the liver as the liver disease progression in many countries might have different influenced factors, especially in chronic viral hepatitis infection due to different genetic polymorphism and different virus genotype distribution. Obesity, which is now becoming one of the biggest problems in NAFLD patients, it would also give a different prognosis in liver disease progression between Western and Asian countries because of different type of food habits and lifestyle. Alcohol consumption issue would become the emerging controversies issue in the near future as NAFLD is now becoming an emerging disease despite chronic viral hepatitis infection.

Remote ischemic preconditioning prevents lipopolysaccharide-induced liver injury through inhibition of NF-κB activation in mice.

Remote ischemic preconditioning (RIPC) is a potent preconditioning stimulus that may confer subsequent protection to organs subjected to potentially lethal injury. The aim of this study was to investigate the effect of RIPC on nuclear factor (NF)-κB activation, tumor necrosis factor (TNF)-α release, and hepatic injury in lipopolysaccharide (LPS)-induced sepsis. This randomized experimental animal study was performed using 8-week-old mice weighing 35-40 g. Mice were randomized (n = 13 per group) to four groups. RIPC was induced with three 10-min cycles of hind limb ischemia by placing an elastic rubber band tourniquet on the proximal part of the limb, with each ischemia cycle followed by 10 min of reperfusion. The groups were treated as follows: (1) the control group received an injection of saline [intraperitoneally (i.p.)]; (2) the RIPC group was subjected to RIPC, followed immediately by an injection of saline (i.p.); (3) the LPS group received an injection of LPS (20 mg/kg, i.p.); (4) the RIPC/LPS group was subjected to RIPC, followed immediately by an injection of LPS (20 mg/kg, i.p.). TNF-α, NF-κB, and IκB-α levels, neutrophil accumulation, and microabscess formation in the liver were evaluated after LPS injection. Among our treatment groups, RIPC significantly attenuated TNF-α release in response to endotoxin and inhibited NF-κB activation, neutrophil accumulation, and microabscess formation in the liver. The results demonstrate that RIPC has protective effects in liver injury via attenuation of TNF-α production in LPS-induced sepsis. The suppressive effect on TNF-α production may be mediated through inhibition of NF-κB activation.

Statins and the risk of liver injury: a population-based case-control study.

This case-control study investigated the association between statin use and liver injury using Taiwan's National Health Insurance Research Database. Our study subjects included 4165 cases (patients who had been admitted with a primary diagnosis of liver injury between 2002 and 2009) and 16 660 age-matched, sex-matched and index date-matched controls. Multivariable conditional regression models were used to estimate the association between statin use and liver injury. Users of statins were not associated with risk of liver injury (adjusted odds ratio [aOR] 1.04; 95% confidence interval [0.90-1.19]) when compared with nonusers. Nevertheless, a higher dose of statin (≥1 defined daily dose; aOR 1.55 [1.14-2.11]) and use of rosuvastatin before event of liver injury (aOR 1.38 [1.03-1.85]) were significantly associated with liver injury. This population-based study extends previous evidence by exploring the potential association between statins use and risk of liver injury. Overall, we found that statin was not associated with risk of liver injury. Nevertheless, special concern should be paid to those who used statin ≥1 defined daily dose and rosuvastatin.

Portal Hypertension and Related Clinical Syndromes

Portal hypertension is characterized by an increased portal pressure gradient which is the difference in pressure between the portal vein and the inferior vena cava and becomes clinically significant when the portal pressure gradient increases to 10 mmHg or above. Portal hypertension is responsible for many of the manifestations of liver cirrhosis. These manifestations such as gastrointestinal bleeding as a result of ruptured gastroesophageal varices and portal hypertensive gastropathy, colopathy and ascites are documented. Hepatorenal syndrome and hypersplenism are the direct consequences of portal hypertension. Stellate cell activation is a key event in liver injury, and indicates the transition from a quiescent vitamin A-rich cell to a highly fibrogenic cell. Activation consists of three major phases: initiation, perpetuation and resolution. Initiation refers to early paracrine-mediated changes in gene expression and phenotype that render the cells responsive to other cytokines and stimuli while perpetuation results from the effects of these stimuli on maintaining the activated phenotype and generating fibrosis. Portal hypertension secondary to hepatic fibrosis and cirrhosis has multisystem effects and multiple complications. The multisystem effects are hepatorenal, portopulmonary hypertension, hepatopulmonary syndrome, portal hypertensive colopathy and others. Once a patient develops any of such complications, he is considered to have decompensated disease with the high morbidity and mortality.

Augmenter of liver regeneration improves therapeutic effect of hepatocyte homotransplantation in acute liver failure rats

Hepatocyte transplantation (HCT) is an available option on treatment for acute liver failure (ALF). However, short-term survival of engraftment and immunological rejections of recipient are major obstacles. Augmenter of liver regeneration (ALR) has cytoprotective and immunoregulatory effects in liver injury, and has been used in many experimental applications. In the present study, we investigated the potential effect and mechanism of recombinant human ALR (rhALR) on ALF rats treated with intraperitoneal HCT. ALF rats induced by d-galactosamine (GalN) were studied in vivo, and were intraperitoneal injected with or without hepatocytes and rhALR 24h after the induction. Animal survival, serum and ascites liver enzymes, tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) were assessed. Histological examination was performed, and liver regeneration, apoptosis and immunological responses were identified by immunohistochemistry assay. Our results showed that rhALR promoted hepatocytes regeneration, attenuated liver injury and suppressed immunological responses. The ascites liver enzyme, serum and ascites pro-inflammatory cytokines (TNF-α, IL-1β), liver histological injury, apoptotic hepatocytes and activated immunocytes were significantly reduced in ALF rats treated with rhALR and HCT compared with those without rhALR. The proliferative and mitotic hepatocytes were markedly increased, and overall survival improved with rhALR. The administration of rhALR improved survival and promoted liver recovery in HCT treatment for ALF, which was associated with the role of proliferative promoter and immunosuppressor. This study suggests that co-treated with rhALR and HCT can provide a promising strategy for the treatment of ALF.

Lamin aggregation is an early sensor of porphyria-induced liver injury

Oxidative liver injury during steatohepatitis results in aggregation and transglutaminase-2 (TG2)-mediated crosslinking of the keratin cytoplasmic intermediate filament proteins (IFs) to form Mallory-Denk body (MDB) inclusions. The effect of liver injury on lamin nuclear IFs is unknown, though lamin mutations in several human diseases result in lamin disorganization and nuclear shape changes. We tested the hypothesis that lamins undergo aggregation during oxidative liver injury using two MDB mouse models: (i) mice fed the porphyrinogenic drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and (ii) mice that harbor a mutation in ferrochelatase (fch), which converts protoporphyrin IX to heme. Dramatic aggregation of lamin A/C and B1 was noted in the livers of both models in association with changes in lamin organization and nuclear shape, as determined by immunostaining and electron microscopy. The lamin aggregates sequester other nuclear proteins including transcription factors and ribosomal and nuclear pore components into high molecular weight complexes, as determined by mass-spectrometry and confirmed biochemically. Lamin aggregate formation is rapid and precedes keratin aggregation in fch livers, and is seen in liver explants of patients with alcoholic cirrhosis. Exposure of cultured cells to DDC, protoporphyrin IX or N-methyl-protoporphyrin, or incubation of purified lamins with protoporphyrin IX, also results in lamin aggregation. In contrast, lamin aggregation is ameliorated by TG2 inhibition. Therefore, lamin aggregation is an early sensor of porphyria-associated liver injury and might serve to buffer oxidative stress. The nuclear shape and lamin defects associated with porphyria phenocopy the changes seen in laminopathies and could result in transcriptional alterations due to sequestration of nuclear proteins.

Characterizing phenotypes and outcomes of drug‐associated liver injury using electronic medical record data

To evaluate the incidence, phenotypes, and outcomes of drug-associated liver injury identified in electronic medical record (EMR) data using standardized criteria for drug-induced liver injury (DILI). This retrospective cohort study used EMR data from a large integrated healthcare system. Study inclusion required 18 years of age or older, ≥1 prescription fill for any of 14 medications associated with hepatotoxicity between 1 January 2003 and 30 June 2009, and ≥12 months of membership prior to the drug exposure. Patients with underlying non-drug causes of liver injury were excluded to minimize capture of liver injury events unrelated to drugs. Drug-associated liver injuries were identified by liver chemistry elevations temporally associated with drug use based on standardized criteria for DILI. Cases were classified by clinical pattern and severity. Outcomes of liver transplant and all-cause and liver-related death were examined. A total of 1 053 979 drug exposures were identified in 601 125 patients. We identified 265 drug-associated liver injuries (32.8 per 100 000 persons) occurring in 250 patients. Isoniazid exhibited the highest incidence rate of 606 per 100 000 persons. Of the 265 cases, 41% were mild; 12% exhibited moderate drug-associated liver injury (with concomitant ALT ≥ 5× ULN and bilirubin ≥2× ULN); and 17% exhibited coagulopathy, ascites, encephalopathy, or other organ failure. Last, seven cases (3%) were associated with death, and there were no liver transplants. Study results align with earlier prospective studies, supporting the value of standardized methodology to identify drug-associated liver injury in the EMR. These methods can potentially enhance safety and clinical outcomes.

Viral-Load-Dependent Effects of Liver Injury and Regeneration on Hepatitis B Virus Replication in Mice

Hepatitis B virus (HBV) is a hepatotropic virus that can cause severe liver diseases. By conducting studies using four different transgenic mouse lines that carry either the wild-type HBV genome or the HBV genome incapable of expressing the X gene, we found that liver injury and regeneration induced by a partial hepatectomy (PHx) could have different effects on HBV replication depending on the mouse lines. Further studies using hydrodynamic injection to introduce different amounts of the HBV genomic DNA into the mouse liver revealed that liver injury and regeneration induced by PHx enhanced HBV replication when viral load was low and suppressed HBV replication when viral load was high. These effects of liver injury and regeneration on HBV were independent of the HBV X protein and apparently due to alpha and beta interferons (IFN-α/β), as the effects could be abolished by the injection of anti-IFN-α/β antibodies. Further analysis indicated that PHx could induce the expression of hepatocyte nuclear factor 3 gamma (HNF3γ) when viral load was low and activate the signal transducer and activator of transcription 3 (Stat3) and suppress the expression of the suppressor of cytokine signaling 3 (SOCS3) irrespective of viral load. As both HNF3γ and Stat3 are required to activate the HBV enhancer I to stimulate HBV gene expression and replication, these results provided an explanation to the viral-load-dependent effect of liver injury and regeneration on HBV replication. Our studies thus revealed a novel interaction between HBV and its host and provided important information for understanding HBV replication and pathogenesis during liver injury.

Enhanced Anti-Diabetic Activity of a Combination of Chromium(III) Malate Complex and Propolis and its Acute Oral Toxicity Evaluation

In order to obtain the additional benefit of anti-diabetic activity and protective effects of liver injury for diabetes, the anti-diabetic effect and acute oral toxicity of a combination of chromium(III) malate complex (Cr(2)(LMA)(3)) and propolis were assessed. The anti-diabetic activity of the combination of the Cr(2)LMA(3) and propolis was compared with Cr(2)(LMA)(3) and propolis alone in alloxan-induced diabetic mice by daily oral gavage for a period of 2 weeks. Acute oral toxicity of the combination of the Cr(2)LMA(3) and propolis was tested using ICR mice at the dose of 1.0-5.0 g/kg body mass by a single oral gavage and observed for a period of 2 weeks. The results of the anti-diabetic activity of the combination from the aspects of blood glucose level, liver glycogen level, and the activities of aspartate transaminase, alanine transaminase, and alkaline phosphatase indicated that the increased anti-diabetic activity and the protective efficacy of liver injury for diabetes were observed. In acute toxicity study, LD(50) (median lethal dose) value for the combination was greater than 5.0 g/kg body mass. The combination of Cr(2)LMA(3) and propolis might represent the nutritional supplement with potential therapeutic value to control blood glucose and exhibit protective efficacy of liver injury for diabetes and non-toxicity in acute toxicity.

High-dose vitamin C: Does it exacerbate the effect of psychosocial stress on liver? Biochemical and histological study

Chronic stress has been implicated as a contributing factor in liver injury. However, other factors that can contribute to the severity of stress effect in liver injury have not been well characterized. In this study, the combined effect of chronic psychosocial stress and variable dosing levels of vitamin C on liver injury, have been studied. Stress was chronically induced using intruder method. Vitamin C was administered by oral gavage. Both biochemical and histopathological measures were undertaken. The results showed that low (50mg/kg/day) and moderate (150 mg/kg/day) doses of vitamin C alone or in combination with chronic stress had no effect on liver. However, combination of high dose of vitamin C (500 mg/kg/day) and chronic stress induced various histopathological liver lesions in most of animals in the group that was stressed and supplemented with high dose vitamin C. Results of this study show a dose-dependent effect for vitamin C in exacerbating stress contribution to liver injury.

Ganoderma lucidum extract attenuates the proliferation of hepatic stellate cells by blocking the PDGF receptor

Hepatic fibrosis is an outcome of chronic liver diseases. The activation and proliferation of hepatic stellate cells (HSCs) is a key event in liver injury. The fruiting body of Ganoderma lucidum has long been a popular oriental medicine for treating liver diseases. The aim of this present study was to investigate the antiproliferative effects of the triterpenoid-rich extract (GLT) of G. lucidum in a cell line of rat HSCs (HSC-T6) stimulated with platelet-derived growth factor (PDGF)-BB. DNA synthesis was investigated by bromodeoxyuridine (BrdU) incorporation. Flow cytometry using propidium iodide (PI) labeling was carried out to analyse the cell cycle distribution and apoptosis. alpha-Smooth muscle actin (alpha-SMA) was used to evaluate extracellular matrix deposition, and western blotting was performed to measure cyclins D1 and D2, and phosphorylation of the PDGFbeta-receptor (PDGFbetaR), Akt and JNK. The results indicated that the GLT attenuated BrdU incorporation in a concentration-dependent manner with an IC(50) of 8.52 +/- 0.33 microg/mL. The inhibitory effect of the GLT was associated with downregulation of cyclins D1 and D2, and PDGFbetaR and Akt phosphorylation, upregulation of JNK phosphorylation, and a reduction in alpha-SMA expression. These results indicated that G. lucidum inhibits PDGF-BB-activated HSC proliferation possibly through blocking PDGFbetaR phosphorylation, thereby indicating its efficacy for preventing and treating hepatic fibrosis.

Further insight into the impact of sodium selenite on selenoenzymes: High-dose selenite enhances hepatic thioredoxin reductase 1 activity as a consequence of liver injury

Selenium (Se) at supranutritional levels can enhance the activity of glutathione S-transferase (GST), whose gene is a target of nuclear factor erythroid-2 related factor 2 (Nrf2). Recent studies indicated that the thioredoxin reductase 1 (TrxR1) gene could also be targeted by Nrf2. Thus, high-dose Se may stimulate TrxR1 provided it enhances GST activity. Indeed, one study found that Se at supranutritional levels transiently increased hepatic TrxR1 activity. However, another study reported that supranutritional Se had no such effect on hepatic TrxR1 activity. In view of this discrepancy, the present research investigated whether high-dose Se has any impact on hepatic TrxR1. Moreover, we investigated whether Se preferentially activates GST over TrxR1. We observed that when sodium selenite (SS) caused liver injury, both hepatic TrxR1 activity and hepatic GST activity increased. Further experiments indicated that SS increased hepatic GST activity at either toxic or high but non-toxic dose levels; however, increase in hepatic TrxR1 activity occurred only at toxic levels, suggesting that enhanced TrxR1 activity correlates with liver injury. To corroborate this, we showed that hepatotoxic agents, thioacetamide or carbon tetrachloride, caused marked increases in hepatic TrxR1 activity. In conclusion, high-dose SS indeed can enhance hepatic TrxR1 activity, but only on the condition that it causes liver injury. High-dose SS affects hepatic GST more readily than hepatic TrxR1. Thus, the cancer-preventive mechanism of Se at non-toxic supranutritional levels relies more on its modulation of GST rather than TrxR1, at least in liver tissue.

Transcriptomic fingerprints of Beta2m−/Thy1+ bone marrow stem cells derived from common bile duct-ligated rats

Introduction: Previously our laboratory identified a population of cells within the bone marrow, known as Beta2m−/Thy1+ bone marrow derived stem cells (BMSC) that are able to differentiate into hepatocytes. The effect of liver injury on the genes expressed by Beta2m−/Thy1+ BMSC is not known. The objective of this study was to determine the gene expression profile of Beta2m−/Thy1+ BMSC in common bile duct-ligated (CBDL) rats using DNA microarray analysis. Methods: Male Lewis rats underwent CBDL (n = 3)or a sham operation (n = 3). After 10 days, their bone marrow was harvested and Beta2m−/Thy1+ BMSC isolated using a two-step magnetic bead cell sorting technique. The mRNA expression profile of primary hepatocytes harvested from sham-operated male Lewis rats (n = 3) was used for comparison. The gene expression profile of Beta2m−/Thy1+ BMSC was determined using Affymetrix rat genemone U34a array. Results: In sham-operated rats, 24 common genes were found between Beta2m-/Thy1+ BMSC and normal hepatocytes. In the CBDL rats, 189 commonly expressed genes were found between the Beta2m-/Thy1+ BMSC and normal hepatocytes. Several liver-specific genes were identified including HNF1, Complement component C3, cholesterol esterase, Cytochrome P50 3A2, D site albumin promoter binding protein and mitochondrial import stimulation factor. Conclusions: Our results demonstrate that liver injury by CBDL alters the gene expression profile of Beta2m-/Thy1+ BMSCs. Cluster analysis of hepatocyte genes revealed Beta2m-/Thy1+ BMSCs from CBDL rats shared more genes in common with primary hepatocytes than Beta2m-/Thy1+ BMSCs from sham-operated rats. Download full-size image

Down-regulation of the organic cation transporter 1 of rat liver in obstructive cholestasis.

The liver plays a major role in biotransformation and elimination of various therapeutic agents and xenobiotics, many of which are organic cations and substrates of the organic cation transporter 1 (Oct1, Slc22a1). Oct1 is expressed at the basolateral membranes of hepatocytes and proximal renal tubules. Although Oct1 is the major uptake mechanism in hepatocytes for many pharmaceutical compounds, little is known about the effects of liver injury on this process. Our aim was to investigate the effects of obstructive cholestasis on Oct1 expression and function in liver and kidney. The effects of bile duct ligation (BDL) on Oct1 protein, messenger RNA (mRNA) expression, and tissue localization were determined in rat liver and kidney with Western analysis, real-time reverse transcriptase-mediated polymerase chain reaction (RT-PCR), and immunofluorescence. To assess Oct1 function, the model substrate tetraethylammonium ([(14)C]TEA) was administered intravenously to BDL and control rats and distribution of radioactivity was determined. Oct1 protein significantly decreased in cholestatic livers to 42.1 +/- 17.7% (P <.001), 15.5 +/- 4.7% (P <.05), and 8.6 +/- 2.7% (P <.05) of controls after 3, 7, and 14 days, respectively, but not in kidneys. Hepatic Oct1 mRNA decreased to 77.2 +/- 12.7%, 40.7 +/- 8.1% (P <.05), and 50.3 +/- 7.5% (P <.05) 3, 7, and 14 days after BDL, respectively. Tissue immunofluorescence corroborated these data. Hepatic accumulation of [(14)C]TEA in 14-day BDL rats was reduced to 29.6 +/- 10.9% of controls (P <.0005). In conclusion, obstructive cholestasis down-regulates Oct1 and impairs Oct1-mediated uptake in rat liver, suggesting that hepatic uptake of small cationic drugs may be impaired in cholestatic liver injury.