Early Liver Injury Research Articles

Decreasing Phosphatidylcholine on the Surface of the Lipid Droplet Correlates with Altered Protein Binding and Steatosis.

Alcoholic fatty liver disease (AFLD) is characterized by an abnormal accumulation of lipid droplets (LDs) in the liver. Here, we explore the composition of hepatic LDs in a rat model of AFLD. Five to seven weeks of alcohol consumption led to significant increases in hepatic triglyceride mass, along with increases in LD number and size. Additionally, hepatic LDs from rats with early alcoholic liver injury show a decreased ratio of surface phosphatidylcholine (PC) to phosphatidylethanolamine (PE). This occurred in parallel with an increase in the LD association of perilipin 2, a prominent LD protein. To determine if changes to the LD phospholipid composition contributed to differences in protein association with LDs, we constructed liposomes that modeled the LD PC:PE ratios in AFLD and control rats. Reducing the ratio of PC to PE increased the binding of perilipin 2 to liposomes in an in vitro experiment. Moreover, we decreased the ratio of LD PC:PE in NIH 3T3 and AML12 cells by culturing these cells in choline-deficient media. We again detected increased association of specific LD proteins, including perilipin 2. Taken together, our experiments suggest an important link between LD phospholipids, protein composition, and lipid accumulation.

Plasma miRNA-122-5p and miRNA-151a-3p identified as potential biomarkers for liver injury among CHB patients with PNALT.

Plasma microRNA (miRNA) levels may be altered during pathological processes; therefore, they may potentially serve as biomarkers for the diagnosis and prognosis of human diseases. This study aimed to explore whether plasma miRNAs may serve as new biomarkers for liver injury among chronic hepatitis B (CHB) patients with normal or nearly normal alanine aminotransferase (ALT) levels. Plasma miRNAs from each of three independent groups (no prominent liver injury and persistently normal ALT levels, NPNALT; significant liver injury with persistently normal ALT levels, SPNALT; and healthy) were profiled by miRNA microarray analysis. Differentially expressed miRNAs were then validated by a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. The area under the receiver operating characteristic (AUC) curve was used to analyze the candidate miRNAs validated by qRT-PCR for diagnostic accuracy. Twenty differentially expressed miRNAs were identified by microarray analysis. Seven miRNAs with elevated serum levels were validated by qRT-PCR analysis, and four of them were significantly different between the SPNALT and NPNALT groups. The AUCs of hsa-miR-122-5p and hsa-miR-151-3p were 0.877 (cutoff value = 13.38; 95% CI 0.792-0.963; sensitivity = 83.3%, specificity = 80%) and 0.882 (cutoff value = 7.4; 95% CI 0.797-0.966; sensitivity = 83.3%, specificity = 73.3%), respectively, indicating early liver injury. However, there was no significant correlation of miRNAs with either necroinflammation or fibrosis. Serum hsa-miR-122-5p and hsa-miR-151-3p may function as new biomarkers for liver injury in SPNALT patients. With these two biomarkers, we may be able to identify a subset of patients who are experiencing liver injury but have normal ALT levels for further evaluation with a biopsy procedure.

Mo1486 - Mitophagy and Oxidative Stress in Early Stage Acetaminophen-Induced Liver Injury

Mo1486 - Mitophagy and Oxidative Stress in Early Stage Acetaminophen-Induced Liver Injury

Hepatotoxicity after paracetamol overdose in a patient with cystic fibrosis despite early acetylcysteine and utility of microRNA to predict hepatotoxicity

Case details: A 19-year-old girl presented to the emergency department following overdose of 10 g of paracetamol on a background history of cystic fibrosis. Paracetamol concentration was below the nomogram line, but was treated with acetylcysteine seven hours post-overdose given her symptomatology. Nineteen hours following her overdose she developed hepatotoxicity, despite early initiation of acetylcysteine. She was discharged well six days post-ingestion. On presentation, delta miRNA-122-miR483 was 20 times that of control patients, however, alanine aminotransferase was normal.Discussion: Patients with cystic fibrosis are more likely to have glutathione deficiency, and greater susceptibility to liver injury. Delta miRNA may be a better detector of early liver injury than hepatic aminotransferases. Empiric treatment with acetylcysteine and serial biochemical reassessment in this setting should be considered.

Long-Term Systematic Monitoring of Four Polish Transaldolase Deficient Patients.

Transaldolase deficiency (TALDO; OMIM 606003) is a rare inborn autosomal recessive error of the pentose phosphate pathway that, to date, has been diagnosed in 33 patients. Tżhere are few reports regarding the long-term follow-up of these patients.The aim of our study is to present the disease progression in the form of a systematic long-term follow-up of four Polish patients with TALDO. We report four patients who manifested early onset TALDO. They were monitored with systematic clinical and laboratory examinations for 4-13years. The dominant feature was an early liver injury, with subsequent renal tubulopathy. All patients presented with osteopenia and poor physical development. Our data shows that polyol concentrations seem to decrease with age. In our patients, a progressive coagulopathy was the most sensitive parameter of liver dysfunction. Nodular fibrosis of the liver developed over the natural course of TALDO. This is the first report of long-term systematic clinical and biochemical monitoring of the disease progress in patients with TALDO.

Mitophagy and oxidative stress in early stage acetaminophen-induced liver injury

Background: Mitochondria go through frequent cycles of fusion and fission, a process required for mitochondrial quality control by eliminating ROS damaged mitochondria through mitophagy. Acetaminophen (APAP) overdose causes liver injury in animals and humans usually by mitochondria damage, which needed further study. Toxicity is mediated by the metabolism of APAP to the reactive metabolite N acetyl-p-benzoquinone imine, which forms adducts on cellular proteins in mitochondria. The aim of the current study is to assess the changes between oxidative stress and companied mitophagy in a rodent model which mimics APAP-induced liver injury (AILI) in humans.

Loss of cellular FLICE-inhibitory protein promotes acute cholestatic liver injury and inflammation from bile duct ligation.

Cholestatic liver injury results from impaired bile flow or metabolism and promotes hepatic inflammation and fibrogenesis. Toxic bile acids that accumulate in cholestasis induce apoptosis and contribute to early cholestatic liver injury, which is amplified by accompanying inflammation. The aim of the current study was to evaluate the role of the antiapoptotic caspase 8-homolog cellular FLICE-inhibitory (cFLIP) protein during acute cholestatic liver injury. Transgenic mice exhibiting hepatocyte-specific deletion of cFLIP (cFLIP-/-) were used for in vivo and in vitro analysis of cholestatic liver injury using bile duct ligation (BDL) and the addition of bile acids ex vivo. Loss of cFLIP in hepatocytes promoted acute cholestatic liver injury early after BDL, which was characterized by a rapid release of proinflammatory and chemotactic cytokines (TNF, IL-6, IL-1β, CCL2, CXCL1, and CXCL2), an increased presence of CD68+ macrophages and an influx of neutrophils in the liver, and resulting apoptotic and necrotic hepatocyte cell death. Mechanistically, liver injury in cFLIP-/- mice was aggravated by reactive oxygen species, and sustained activation of the JNK signaling pathway. In parallel, cytoprotective NF-κB p65, A20, and the MAPK p38 were inhibited. Increased injury in cFLIP-/- mice was accompanied by activation of hepatic stellate cells and profibrogenic regulators. The antagonistic caspase 8-homolog cFLIP is a critical regulator of acute, cholestatic liver injury. NEW & NOTEWORTHY The current paper explores the role of a classical modulator of hepatocellular apoptosis in early, cholestatic liver injury. These include activation of NF-κB and MAPK signaling, production of inflammatory cytokines, and recruitment of neutrophils in response to cholestasis. Because these signaling pathways are currently exploited in clinical trials for the treatment of nonalcoholic steatohepatitis and cirrhosis, the current data will help in the development of novel pharmacological options in these indications.

Kupffer cells activation promoted binge drinking-induced fatty liver by activating lipolysis in white adipose tissues.

Kupffer cells (KCs) have been suggested to play critical roles in chronic ethanol induced early liver injury, but the role of KCs in binge drinking-induced hepatic steatosis remains unclear. This study was designed to investigate the roles of KCs inhibitor (GdCl3) and TNF-α antagonist (etanercept) on binge drinking-induced liver steatosis and to explore the underlying mechanisms. C57BL/6 mice were exposed to three doses of ethanol (6g/kg body weight) to mimic binge drinking-induced fatty liver. The results showed that both GdCl3 and etanercept partially but significantly alleviated binge drinking-induced increase of hepatic triglyceride (TG) level, and reduced fat droplets accumulation in mice liver. GdCl3 but not etanercept significantly blocked binge drinking-induced activation of KCs. However, neither GdCl3 nor etanercept could affect binge drinking-induced decrease of PPAR-α, ACOX, FAS, ACC and SCD protein levels, or increase of the LC3 II/LC3 I ratio and p62 protein level. Interestingly, both GdCl3 and etanercept significantly suppressed binge drinking-induced phosphorylation of HSL in epididymal adipose tissues. Results of in vitro studies with cultured epididymal adipose tissues showed that TNF-α could increase the phosphorylation of HSL in adipose tissues and upgrade the secretion of free fatty acid (FFA) in the culture medium. Taken together, KCs inhibitor and TNF-α antagonist could partially attenuate binge drinking-induced liver steatosis, which might be attributed to the suppression of mobilization of white adipose tissues. These results suggest that KCs activation may promote binge drinking-induced fatty liver by TNF-α mediated activation of lipolysis in white adipose tissues.

Effects of three different concentrations of hypertonic sodium salt resuscitation on liver injury of rats at the early stage of severe burned

To investigate the effects of three different concentrations of hypertonic sodium salt (HS) resuscitation on liver injury of rats at the early stage of severe burned. 104 female Sprage-Dawley (SD) rats were randomly divided into five groups: sham group (n = 8), lactated Ringer solution (LR) group (n = 24), 600, 800, 1 000 mmol/L HS groups (HS600, HS800, and HS1000 groups, n = 24). Rats in LR group and HS groups were subjected to full-thickness scald with 30% total body surface area (TBSA), and then given liquid resuscitation treatment with LR and the corresponding HS. These rats were sacrificed at 2, 8 and 24 hours post injury to collect blood and liver tissue. Rats in sham group were given simulation of burns without resuscitation, which were immediately sacrificed and the specimens were harvested. The levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were detected by automatic biochemical analyzer. The levels of liver tissue malondialdehyde (MDA) and superoxide dismutase (SOD) were detected by ultraviolet spectrophotometry. The expression of liver tissue p38 mitogen-actirated protein kinase (p38MARK) was detected by Western Blot. Compared with sham group, the levels of ALT, AST, MDA and p38MAPK were increased, and the activities of SOD were decreased in LR group and different degrees in HS groups at each time point after injury. Compared with LR group, the levels of ALT, AST, MDA and p38MAPK were decreased and the activities of SOD were increased in different degrees with HS groups, among which HS600 group changed most significantly [ALT (U/L): 147±52 vs. 227±60 at 8 hours, 138±47 vs. 191±41 at 24 hours; AST (U/L): 288±79 vs. 548±237 at 2 hours, 567±167 vs. 841±338 at 8 hours, 515±180 vs. 712±159 at 24 hours; MDA (nmol/mg): 0.287±0.036 vs. 0.395±0.041 at 2 hours, 0.298±0.030 vs. 0.392±0.018 at 8 hours, 0.278±0.033 vs. 0.422±0.036 at 24 hours; SOD (U/mg): 230±16 vs. 159±30 at 2 hours, 251±14 vs. 194±15 at 8 hours, 296±8 vs. 243±11 at 24 hours; p-p38MAPK/p38MAPK (A value): 0.778±0.040 vs. 1.065±0.066 at 2 hours, 0.791±0.046 vs. 0.967±0.041 at 8 hours, 0.733±0.027 vs. 1.020±0.043 at 24 hours; all P < 0.05]. The levels of ALT and AST in HS600 group were significantly lower than those in HS1000 group at 2 hours and in HS800 group at 8 hours. The levels of MDA and p38MAPK in HS600 group were significantly lower than those of HS800 group and HS1000 group, and the level of SOD in HS600 group was significantly higher than that in HS800 group and HS1000 group at each time point after injury. There were no significant differences in all test indicators between HS800 group and HS1000 group at each time point after injury. High concentration of HS can reduce the early liver injury in severely scalded rats, of which the curative effect of HS 600 mmol/L is best.

Autophagy and ER stress in LPS/GalN‑induced acute liver injury.

Numerous mechanisms and factors have been implicated in liver damage; however, the involvement of autophagy and endoplasmic reticulum (ER) stress during early‑stage liver injury remains to be fully elucidated. The present study was conducted to determine the expression of autophagy and ER‑stress‑associated proteins in hepatic tissues following injury. A murine model of liver injury was induced by intraperitoneally injecting lipopolysaccharide (LPS) and D‑galactosamine (GalN), and control mice were similarly injected with normal saline. The gross and histological appearance of the liver was examined, serum alanine aminotransferase (ALT) levels were detected, and protein expression evaluated via Western blot analysis. Co‑administration of LPS and GalN effectively induced liver injury in mice, with severe liver damage manifesting at 6h following induction. Furthermore, upregulation of autophagy‑associated proteins, including microtubule‑associated protein 1 light chain 3 (MAP1 LC3 or, briefly, LC3‑II) and Beclin 1, were detected 3h following liver injury. Consistently, the expression of the ER stress factor CCAAT/enhancer binding protein (C/EBP)‑homologous protein decreased after 1h, but increased 3h after liver damage. Autophagy and ER stress occurred in early‑stage liver injury induced by LPS‑GalN administration in mice. Induction of autophagy may act as a compensatory mechanism during early liver injury.

NOX4 Regulates CCR2 and CCL2 mRNA Stability in Alcoholic Liver Disease

Recruitment of inflammatory cells is a major feature of alcoholic liver injury however; the signals and cellular sources regulating this are not well defined. C-C chemokine receptor type 2 (CCR2) is expressed by active hepatic stellate cells (HSC) and is a key monocyte recruitment signal. Activated HSC are also important sources of hydrogen peroxide resulting from the activation of NADPH oxidase 4 (NOX4). As the role of this NOX in early alcoholic liver injury has not been addressed, we studied NOX4-mediated regulation of CCR2/CCL2 mRNA stability. NOX4 mRNA was significantly induced in patients with alcoholic liver injury, and was co-localized with αSMA-expressing activated HSC. We generated HSC-specific NOX4 KO mice and these were pair-fed on alcohol diet. Lipid peroxidation have not changed significantly however, the expression of CCR2, CCL2, Ly6C, TNFα, and IL-6 was significantly reduced in NOX4HSCKO compared to fl/fl mice. NOX4 promoter was induced in HSC by acetaldehyde treatment, and NOX4 has significantly increased mRNA half-life of CCR2 and CCL2 in conjunction with Ser221 phosphorylation and cytoplasmic shuttling of HuR. In conclusion, NOX4 is induced in early alcoholic liver injury and regulates CCR2/CCL2 mRNA stability thereby promoting recruitment of inflammatory cells and production of proinflammatory cytokines.

TNF-α and Interleukin-6 Levels in Clinical Early Onset Neonatal Sepsis Toward Acute Liver Injury

TNF-α and IL-6 level have an important role in acute liver injury during early onset neonatal sepsis. This study aims to investigate the correlation of TNF-α and IL-6 levels in neonates with clinical early onset neonatal sepsis toward the occurrence of acute liver injury 44 neonates with clinical early onset neonatal sepsis based on SIRS criteria and Rodwell hematologic scored ≥3 were included in this study. Acute liver injury is defined as elevated of AST, ALT, or AST: ALT ratio &lt;1. TNF-α and IL-6 levels were measured using ELISA methods. This study showed that TNF-α correlated significantly with AST level (p&lt;0,001, r=0,570), ALT level (p&lt;0,001, r=0,554), and AST: ALT ratio (p&lt;0,001, r=0,652). This study also showed that IL-6 correlated significantly with AST level (p&lt;0,001, r=0,523), ALT level (p&lt;0,001, r=0,482), AST: ALT ratio (p&lt;0,001, r=0,603). Regression test using backward methods showed that TNF-α influence acute liver injury (indicated by AST, ALT, and AST: ALT ratio) more than IL-6. We concluded that TNF-α and IL-6 level in clinical early onset neonatal sepsis correlated with acute liver injury, whereas early onset neonatal sepsis was correlated with acute liver injury.Keywords: Acute liver injury, clinical early neonatal sepsis, IL-6 level, TNF-α level

Metabolomic Characterizations of Liver Injury Caused by Acute Arsenic Toxicity in Zebrafish.

Arsenic is one of the most common metalloid contaminants in groundwater and it has both acute and chronic toxicity affecting multiple organs. Details of the mechanism of arsenic toxicity are still lacking and profile studies at metabolic level are very limited. Using gas chromatography coupled with mass spectroscopy (GC/MS), we first generated metabolomic profiles from the livers of arsenic-treated zebrafish and identified 34 significantly altered metabolite peaks as potential markers, including four prominent ones: cholic acid, glycylglycine, glycine and hypotaurine. Combined results from GC/MS, histological examination and pathway analyses suggested a series of alterations, including apoptosis, glycogenolysis, changes in amino acid metabolism and fatty acid composition, accumulation of bile acids and fats, and disturbance in glycolysis related energy metabolism. The alterations in glycolysis partially resemble Warburg effect commonly observed in many cancer cells. However, cellular damages were not reflected in two conventional liver function tests performed, Bilirubin assay and alanine aminotransferase (ALT) assay, probably because the short arsenate exposure was insufficient to induce detectable damage. This study demonstrated that metabolic changes could reflect mild liver impairments induced by arsenic exposure, which underscored their potential in reporting early liver injury.

Soluble IgM links apoptosis to complement activation in early alcoholic liver disease in mice.

Ethanol feeding in mice activates complement via C1q binding to apoptotic cells in the liver; complement contributes to ethanol-induced inflammation and injury. Despite the critical role of C1q in ethanol-induced injury, the mechanism by which ethanol activates C1q remains poorly understood. Secretory IgM (sIgM), traditionally considered to act as an anti-microbial, also has critical housekeeping functions, facilitating clearance of apoptotic cells, at least in part through activation of C1q. Therefore, we hypothesized that (1) ethanol-induced apoptosis in the liver recruits sIgM, facilitating the activation of C1q and complement and (2) C1INH (C1 esterase inhibitor), which inhibits C1 functional activity, prevents complement activation and decreases ethanol-induced liver injury. Female C57BL/6 wild-type, C1qa(-/-), BID(-/-) and sIgM(-/-) mice were fed ethanol containing liquid diets or pair-fed control diets. C1INH or vehicle was given via tail vein injection to ethanol- or pair-fed wild-type mice at 24 and 48h prior to euthanasia. Ethanol exposure increased apoptosis in the liver, as well as the accumulation of IgM in the liver. In the early stages of ethanol feeding, C1q co-localized with IgM in the peri-sinusoidal space of the liver and accumulation of IgM and C3b was dependent on ethanol-induced BID-dependent apoptosis. sIgM(-/-) mice were protected from both ethanol-induced activation of complement and early ethanol-induced liver injury when compared to wild-type mice. Treatment with C1INH also decreased hepatic C3b deposition and ethanol-induced injury. These data indicate that sIgM contributes to activation of complement and ethanol-induced increases in inflammatory cytokine expression and hepatocyte injury in the early stages of ethanol-induced liver injury.

Melatonin protects against burn-induced hepatic oxidative injury by inducing HO-1 via the Nrf2 pathway

Melatonin exerts beneficial effects on early liver injury by modulating hepatic oxidative stress. In order to understand the protective effect of melatonin against burn-induced hepatic injury we investigated the expression of 4-hydroxynonenal (4-HNE), a main product of lipid peroxidation and mediator of oxidative injury, the inducible heme-oxygenase-1 (HO-1), an antioxidant enzyme, and the anti-oxidative stress regulator erythroid 2-related factor 2 (Nrf2) in a burn rat model. Expression and localisation of HO-1, 4-HNE and Nrf2 in liver were investigated using light immunochemistry. Thermal skin injury caused a significant elevation in hepatic 4-HNE and degenerative liver changes. Concurrently, there was increased expression of HO-1, a rate-limiting enzyme for haem degradation and an oxidative stress marker in sinusoidal endothelial cells (SECs) and hepatocytes without changes in Nrf2 expression in the liver. Melatonin (20 mg/kg b.w.) augmented the increase in HO-1 expression, upregulated Nrf2 expression and also led to decreased 4-HNE levels and reduced levels of histopathological changes in rat liver. In conclusion, our results suggest that melatonin ameliorates burn-induced liver injury through the inhibition of oxidative stress, upregulation of the antioxidant enzyme HO-1 and activation of the antioxidant Nrf2 pathway. Stimulation of cellular protective mechanisms by activating the antioxidant stress response through Nrf2 is a new mechanism for protection against liver damage in burns.

Drug-induced liver injury: the dawn of biomarkers?

Drug-induced liver injury (DILI) is a potentially fatal adverse event with significant medical and economic impact. Many drugs, especially anti-infective, neurologic or pain-modifying substances, act as hepatotoxins. With cardiovascular toxicity, liver toxicity is one of the two leading causes for drug withdrawal from the market. The liver can be affected directly, in a predictable and dose-dependent manner, or idiosyncratically, independent of the dose and therefore unpredictable.Currently DILI is a diagnosis of exclusion that physicians have to bear in mind in patients with an unexplained increase of liver enzymes. The type of injury is categorized into hepatocellular, cholestatic, or mixed by the respective enzyme pattern of injury. Symptoms of affected patients can mimic any other liver disease.Therefore, new diagnostic and prognostic biomarkers for early liver injury are currently being evaluated in multi-centre clinical trials that are conducted by international consortia and other initiatives. Pharmacogenetic testing, next-generation sequencing, proteomics, metabolomics and mechanistic markers can help to preselect susceptible patient populations and tailor drug therapy to individual patients. Proposed DILI indicators that are under investigation include microRNAs, cytokeratin-18 (CK18), high mobility group box protein 1 (HMGB-1), and several other biomarkers. These developments can change clinical practice, and improve patients' safety and management. However, they have not been translated into clinical practice or approved for routine use yet. Management of DILI usually consists of initial withdrawal of the suspected drug and—if applicable—administration of specific antidotes, such as N-acetylcysteine. However, the overall management of DILI could change in the near future with the advent of novel diagnostic and prognostic DILI markers.

Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration.

Neutrophil infiltration is a hallmark of alcoholic steatohepatitis; however, the underlying mechanisms remain unclear. We previously reported that chronic-plus-binge ethanol feeding synergistically induces hepatic recruitment of neutrophils, which contributes to liver injury. In this paper, we investigated the roles of invariant natural killer T (iNKT) cells in chronic-plus-binge ethanol feeding-induced hepatic neutrophil infiltration and liver injury. Wild-type and two strains of iNKT cell-deficient mice (CD1d- and Jα18-deficient mice) were subjected to chronic-plus-binge ethanol feeding. Liver injury and inflammation were examined. Chronic-plus-binge ethanol feeding synergistically increased the number of hepatic iNKT cells and induced their activation, compared with chronic feeding or binge alone. iNKT cell-deficient mice were protected from chronic-plus-binge ethanol-induced hepatic neutrophil infiltration and liver injury. Moreover, chronic-plus-binge ethanol feeding markedly upregulated the hepatic expression of several genes associated with inflammation and neutrophil recruitment in wild-type mice, but induction of these genes was abrogated in iNKT cell-deficient mice. Importantly, several cytokines and chemokines (e.g., MIP-2, MIP-1, IL-4, IL-6 and osteopontin) involved in neutrophil infiltration were upregulated in hepatic NKT cells isolated from chronic-plus-binge ethanol-fed mice compared to pair-fed mice. Finally, treatment with CD1d blocking antibody, which blocks iNKT cell activation, partially prevented chronic-plus-binge ethanol-induced liver injury and inflammation. Chronic-plus-binge ethanol feeding activates hepatic iNKT cells, which play a critical role in the development of early alcoholic liver injury, in part by releasing mediators that recruit neutrophils to the liver, and thus, iNKT cells represent a potential therapeutic target for the treatment of alcoholic liver disease.

MONITORING EARLY RADIATION-INDUCED LIVER INJURY USING FERUCARBOTRAN-ENHANCED MRI AT 3 T: AN ANIMAL MODEL

The aim of this study was to find the time window for monitoring early radiation-induced liver injury (RILI) of rats using ferucarbotran-enhanced magnetic resonance imaging (MRI) at 3 T. Six rats were irradiated with 20 Gy 6 MV X-ray on right side liver and the other six non-irradiated rats were used as the control. Three or four days after irradiation, the rats were examined using MRI. The conventional spin echo (CSE) pulse sequence with various scanning parameters (CSE1: TR/TE = 200/8 ms, CSE2: TR/TE = 1000/8 ms and CSE3: TR/TE = 1000/22 ms) was performed before, 20 min, 1 h, 7 days, 14 days and 21 days after injecting 80 μmol/kg ferucarbotran, a kind of commercialized superparamagnetic iron oxide (SPIO). The ferucarbotran particles were macrophaged by Kupffer cells and this caused decreased signal intensity on MR images because of the T2and susceptibility effect. The irradiated liver had less reduction of MR signal intensity than the non-irradiated liver because radiation impaired the function of Kupffer cells. All CSE images of the irradiated group showed higher right-to-left ratio of the MR signal intensity in the liver than the control group after ferucarbotran injection. Furthermore, CSE2 demonstrated higher efficacy than CSE1 and CSE3. The optimal time window to observe an obvious contrast between the right side and left side liver in the irradiated group was from 20 min to 7 days after a single bolus injection of ferucarbotran. This protocol may be helpful to investigate the effects of radioprotectors and radiosensitizers on the reticuloendothelial system.

The Frequent Adiponutrin (PNPLA3) Variant p.Ile148Met Is Associated with Early Liver Injury: Analysis of a German Pediatric Cohort

Introduction. The common adiponutrin (PNPLA3) variant p.Ile148Met is associated with liver injury. Here, we investigate the association of this polymorphism with hepatic and metabolic traits in a pediatric cohort. Patients and Methods. The study cohort comprised 142 German children (age 5–9 years, 98 overweight, 19 children with NAFLD). Results. Overweight children presented with increased serum ALT (P = 0.001) and GGT (P < 0.001) activities. ALT activities differed significantly (P = 0.02) between carriers of different PNPLA3 genotypes in the entire study cohort, in normal weight children (P = 0.02) and in children younger than 7 years (P = 0.02). Carriers of the prosteatotic PNPLA3 genotype p.148Met/Met displayed higher ALT activities as compared to children with the frequent genotype p.148Ile/Ile (P = 0.01). The BMI was however a stronger predictor of ALT activities compared to the PNPLA3 genotype (P < 0.001 and P = 0.06, resp.). The variant was associated with increased serum glucose levels (P = 0.01) and HOMA index (P = 0.02) in carriers of the p.148Ile/Met genotype but did not affect other metabolic traits or the presence of NAFLD. Discussion. The frequent PNPLA3 variant p.Ile148Met is associated with serum ALT activities already at a young age.

Protective effect of corn peptides against alcoholic liver injury in men with chronic alcohol consumption: a randomized double-blind placebo-controlled study.

BackgroundCorn peptides (CPs) are a novel food prepared from corn gluten meal, which is a main by-product of the corn starch industry. Recently, significant beneficial effects of CPs on early alcoholic liver injury in rats and on acute alcoholic injury in mice were observed. To our knowledge, the present study is the first report showing that CPs supplementation has beneficial effects on lipid profile, oxidative stress and alcoholic liver injury in men with chronic alcohol consumption.MethodsA 9-week, randomized, double-blind, placebo-controlled study was conducted between September 2011 and August 2012 to assess the hepatoprotective effect of CPs. A total of 161 men were randomized to receive CPs (n = 53), whey protein (n = 54), or corn starch placebo (n = 54) at the same dose of 2 g twice daily. 146 participants completed the study. Serum lipid profile, serum markers of liver injury, oxidative stress and inflammation, and fatty liver based on the results of abdominal ultrasonography were assessed at the beginning and end of the intervention.ResultsCPs supplementation (4 g/d) for 9 weeks significantly lowered serum levels or activities of total cholesterol, triglyceride, alanine aminotransferase, aspartate aminotransferase, malondialdehyde and tumor necrosis factor-α, and significantly increased serum activities of superoxide dismutase and glutathione peroxidase, but the same dose of whey protein and corn starch (placebo) did not demonstrate these effects.ConclusionsOur results indicate that CPs may have protective effects on alcohol-induced liver damage via modulation of lipid metabolism and oxidative stress. CPs may potentially be used as a functional food for the management of alcoholic liver disease in subjects with chronic alcohol consumption.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-511X-13-192) contains supplementary material, which is available to authorized users.