Aggravated Liver Damage Research Articles

N-glycosylation of CREBH improves lipid metabolism and attenuates lipotoxicity in NAFLD by modulating PPARα and SCD-1.

Cyclic adenosine monophosphate (AMP)-responsive element-binding protein H (CREBH), an endoplasmic reticulum-anchored transcription factor essential for lipid metabolism and inflammation in nonalcoholic fatty liver disease (NAFLD), is covalently modified by N-acetylglucosamine. Glycosylationis a ubiquitous type of protein involved in posttranslational modifications, and plays a critical role in various biological processes. However, the mechanism of glycosylated CREBH remains poorly understood in NAFLD. CREBH glycosylation mutants were obtained by site-mutation methods. After transfection with plasmids, AML-12, LO2, or HepG2 cells were treated with palmitic acid (PA) proteolysis, tunicamycin (Tm), or their combination. Glycosyltransferase V (GnT-V) was used induce hyperglycosylation to further understand the effect of CREBH. In addition, glycosylation mutant mice and hyperglycosylated mice were generated by lentivirus injection to construct two kinds of NAFLD animal models. The expression of NAFLD-related factors was detected to further verify the role of N-linked glycosylation of CREBH in lipid and sterol metabolism, inflammation, and lipotoxicity. N-glycosylation enhanced the ability of CREBH to activate transcription and modulated the production of peroxisome proliferator-activated receptor alpha (PPARα) and stearoyl-CoA desaturase-1 (SCD-1) activity by affecting their promoter-driven transcription activity and protein interactions, leading to reduce lipid deposition and attenuate lipotoxicity. Deglycosylation of CREBH induced by Tm could inhibit the proteolysis of CREBH induced by PA. The addition of unglycosylated CREBH to cells upregulates gene and protein expression of lipogenesis, lipotoxicity, and inflammation, and aggravates liver damage by preventing glycosylation in cells, as well as in mouse models of NAFLD. Furthermore, increased N-glycosylation of CREBH, as achieved by overexpressing GnT-V could significantly improve liver lesion caused by unglycosylation of CREBH. These findings have important implications for the role of CREBH N-glycosylation in proteolytic activation, and they provide the first link between N-glycosylation of CREBH, lipid metabolism, and lipotoxicity processes in the liver by modulating PPARα and SCD-1. These results provide novel insights into the N-glycosylation of CREBH as a therapeutic target for NAFLD.

Aryl Hydrocarbon Receptor Activity in Hepatocytes Sensitizes to Hyperacute Acetaminophen-Induced Hepatotoxicity in Mice.

Background & AimsAcetaminophen (APAP)-induced liver injury is one of the most common causes of acute liver failure, however, a clear definition of sensitizing risk factors is lacking. Here, we investigated the role of the ligand-activated transcription factor aryl hydrocarbon receptor (Ahr) in APAP-induced liver injury. We hypothesized that Ahr, which integrates environmental, dietary, microbial and metabolic signals into complex cellular transcriptional programs, might act as a rheostat for APAP-toxicity.MethodsWildtype or conditional Ahr knockout mice lacking Ahr in hepatocytes (AlbΔ/ΔAhr) or myeloid cells (LysMΔ/ΔAhr) were treated with the specific Ahr ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) together with APAP.ResultsAhr activation by ITE, which by itself was non-toxic, exacerbated APAP-induced hepatotoxicity compared to vehicle-treated controls, causing 80% vs. 0% mortality after administration of a normally sublethal APAP overdose. Of note, Ahr activation induced hepatocyte death even at APAP doses within the therapeutic range. Aggravated liver injury was associated with significant neutrophil infiltration; however, lack of Ahr in myeloid cells did not protect LysMΔ/ΔAhr mice from exacerbated APAP hepatotoxicity. In contrast, AlbΔ/ΔAhr mice were largely protected from ITE-induced aggravated liver damage, indicating that Ahr activation in hepatocytes, but not in myeloid cells, was instrumental for disease exacerbation. Mechanistically, Ahr activation fueled hepatic accumulation of toxic APAP metabolites by up-regulating expression of the APAP-metabolizing enzyme Cyp1a2, a direct Ahr downstream target.ConclusionsAhr activation in hepatocytes potentiates APAP-induced hepatotoxicity. Thus, individual exposition to environmental Ahr ligands might explain individual sensitivity to hyperacute liver failure.

Vitamin D and non-alcoholic fatty liver disease in children

Objective The aim of this study was to explore the serum 25-(OH)Vitamin D and its correlation with liver function in children who have suffered from non-alcoholic fatty liver disease(NAFLD), and to explore the necessity of vitamin D treatment of NAFLD in children. Methods Forty children with NAFLD diagnosed by imaging were selected from the outpatient of pediatric digestive department of Shengjing Hospital of China Medical University, selected as observation group from July 2017 to August 2019, and 37 healthy children were selected as control group.The clinical data were collected and serum 25-(OH)Vitamin D were detected at the same time. Results There was no significant difference in 25-(OH)Vitamin D among children with NAFLD at different ages and gender(P>0.05). The level of 25-(OH)Vitamin D in children with NAFLD[(21.30±8.77)μg/L]was significantly lower than that in the control group[(28.53±10.18)μg/L](t=3.343, P<0.01). The incidence of vitamin D deficiency(<20 μg/L)and insufficiency(<30 μg/L)in children with NAFLD(35/40=87.50%)was significantly higher than that in the control group(22/37=59.46%)(χ2=10.035, P<0.05). Serum 25-(OH)Vitamin D was negatively correlated with fasting insulin(r=-0.464, P<0.01)and homeostasis model assessment of insulin resistance(r=-0.444, P<0.01), but not correlated with BMI, transaminase level(ALT, AST), uric acid and blood lipid(TG, TC, HDL-C, LDL-C, sd-LDL, Apo-A1, Apo-B). Vitamin D deficiency was the risk factor of NAFLD(OR=1.088, P<0.01). Conclusion Vitamin D deficiency is common in pediatric NAFLD, which may be a risk factor of NAFLD.The mechanism may be that vitamin D deficiency aggravates insulin resistance and further aggravates liver damage in children with NAFLD. Key words: Children; Non-alcoholic fatty liver disease; 25-(OH)Vitamin D

The study of the functional state of endothelium in patients with chronic viral Hepatitis C

Hepatitis C is the leader among hepatotropic infections in developed countries, where 1- 24% of the population is infected. Currently, the pathological mechanisms controlling the rapid progression of the disease are being actively studied and increased sensitivity to oxidative stress may play a role in this. As a result violation of lipid peroxidation (LPO) processes occur. Increased levels of lipid peroxidation contribute to the development of endothelial function, which aggravates liver damage and contributes to the progression of liver fibrosis.

A High-Calorie Diet Aggravates Mitochondrial Dysfunction and Triggers Severe Liver Damage in Wilson Disease Rats.

Background & AimsIn Wilson disease, ATP7B mutations impair copper excretion into bile. Hepatic copper accumulation may induce mild to moderate chronic liver damage or even acute liver failure. Etiologic factors for this heterogeneous phenotype remain enigmatic. Liver steatosis is a frequent finding in Wilson disease patients, suggesting that impaired copper homeostasis is linked with liver steatosis. Hepatic mitochondrial function is affected negatively both by copper overload and steatosis. Therefore, we addressed the question of whether a steatosis-promoting high-calorie diet aggravates liver damage in Wilson disease via amplified mitochondrial damage.MethodsControl Atp7b+/- and Wilson disease Atp7b-/- rats were fed either a high-calorie diet (HCD) or a normal diet. Copper chelation using the high-affinity peptide methanobactin was used in HCD-fed Atp7b-/- rats to test for therapeutic reversal of mitochondrial copper damage.ResultsIn comparison with a normal diet, HCD feeding of Atp7b-/- rats resulted in a markedly earlier onset of clinically apparent hepatic injury. Strongly increased mitochondrial copper accumulation was observed in HCD-fed Atp7b-/- rats, correlating with severe liver injury. Mitochondria presented with massive structural damage, increased H2O2 emergence, and dysfunctional adenosine triphosphate production. Hepatocellular injury presumably was augmented as a result of oxidative stress. Reduction of mitochondrial copper by methanobactin significantly reduced mitochondrial impairment and ameliorated liver damage.ConclusionsA high-calorie diet severely aggravates hepatic mitochondrial and hepatocellular damage in Wilson disease rats, causing an earlier onset of the disease and enhanced disease progression.

Mannan-binding lectin deficiency exacerbates sterile liver injury in mice through enhancing hepatic neutrophil recruitment.

Noninfectious liver injury, including the effects of drugs and diet, is a major cause of liver diseases worldwide. The innate inflammatory response to hepatocyte death plays a crucial role in the outcome of liver injury. Mannan-binding lectin (MBL) is a pattern recognition molecule of the innate immune system, which is primarily produced by liver. MBL deficiency occurs with high frequency in the population and is reported associated with predisposition to infectious diseases. We here observed that genetic MBL ablation strongly sensitizes mice to sterile liver injury induced by carbon tetrachloride (CCl4 ). Aggravated liver damage was shown in CCl4 -administrated MBL-/- mice, as evidenced by severe hepatocyte death, elevated serum alanine aminotransferase and lactate dehydrogenase activity, and enhanced production of inflammatory cytokines. Mechanistic studies established that MBL deficiency caused increased chemokine CXCL2 production from liver macrophages upon CCl4 stimulation, thereby promoting the hepatic recruitment of neutrophils and subsequent liver damage. Furthermore, MBL-mediated protection from CCl4 -induced liver injury was validated by administration of an MBL-expressing liver-specific adeno-associated virus, which effectively ameliorated the hepatic damage in CCl4-treated MBL-/- mice. We propose that MBL may be exploited as a new therapeutic approach in the treatment of chemical-induced sterile liver injury in patients with MBL deficiency.

Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice.

Matrix remodeling associated 7 (MXRA7) was first noted to co-express with a group of matrix remodeling related genes, and its biological functions had remained unclear. In this study, we investigated the presumed function of MXRA7 in a carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Wild-type, MXRA7−/− mice, and mice that were pulsed with hydrodynamic injection of vehicle or MXRA7-harboring plasmids were challenged with a single dose of CCl4 for injury induction. The sera, spleens, and livers were harvested from mice for assay of cytokines/chemokines expression, cellular responses, or histological features. We found that MXRA7 deficiency alleviated, and MXRA7 overexpression aggravated liver damage in CCl4-challenged mice. FACS analysis showed that MXRA7 deficiency reduced the recruitment of neutrophils through downregulation the expression of CXCL1 and CXCL2 in liver, decreased the number of CD8+ T cells in liver and spleen, suppressed the release of IFNγ and TNFα from T cells, and decreased IFNγ in serum and liver. Western blot assay demonstrated that MXRA7 deficiency suppressed the activation of MAPK pathway and AKT/NF-κB pathway, respectively. Lastly, MXRA7 deficiency or overexpression regulated the expression of two matrix remodeling-related genes (fibronectin and TIMP1) in the liver. We concluded that MXRA7 was an active player in CCl4-induced liver injury, hypothetically by mediating the inflammation or immune compartments and matrix remodeling processes. Further exploration of MXRA7 as a possible new therapeutic target for management of inflammation-mediated liver injury was discussed.

The Role of Autophagy in Critical Illness-induced Liver Damage

Mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which activates the unfolded protein response (UPR), mediate critical illness-induced organ failure, often affecting the liver. Autophagy is known to alleviate both and suppressed or insufficiently activated autophagy in prolonged illness has shown to associate with organ failure. Whether insufficient autophagy contributes to organ failure during critical illness by affecting these underlying mechanisms is incompletely understood. In this study, we investigated whether the inability to acutely activate hepatic autophagy during critical illness aggravates liver damage by increasing hepatic mitochondrial dysfunction and affecting the UPR. In a mouse model of critical illness, induced by surgery and sepsis, we investigated the impact of inactivating hepatic autophagy on markers of hepatic mitochondrial function, the UPR and liver damage in acute (1 day) and prolonged (3 days) critical illness. Hepatic autophagy inactivation during critical illness acutely worsened mitochondrial dysfunction and time-dependently modulated the hepatic UPR. Furthermore, autophagy inactivation aggravated markers of liver damage on both time points. In conclusion, the inability to acutely activate autophagy in liver during critical illness worsened hepatic mitochondrial damage and dysfunction, partially prohibited acute UPR activation and aggravated liver damage, indicating that autophagy is crucial in alleviating critical illness-induced organ failure.

Wisp2 disruption represses Cxcr4 expression and inhibits BMSCs homing to injured liver.

Liver regeneration/repair is a compensatory regrowth following acute liver failure, and bone marrow-derived mesenchyme stem cell (BMSC) transplantation is an effective therapy that promotes liver regeneration/repair. Wnt1 inducible signaling pathway protein 2 (Wisp2) is highly expressed in BMSCs, however, its function remains unclear. In this work, we used clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein -9 nuclease (CRISPR/Cas9) genome editing technology to knockdown Wisp2 in BMSCs, and these modified cells were then transplanted into rats which were induced by the 2-AAF/PH. By linking the expression of Cas9 to green fluorescent protein (GFP), we tracked BMSCs in the rats. Disruption of Wisp2 inhibited the homing of BMSCs to injured liver and aggravated liver damage as indicated by remarkably high levels of ALT and AST. Moreover, the key factor in BMSC transplantation, C-X-C chemokine receptor type 4 (Cxcr4), was down-regulated in the Wisp2 depleted BMSCs and had a lower expression in the livers of the corresponding rats. By tracing the GFP marker, more BMSCs were observed to differentiate into CD31 positive endothelial cells in the functional Wisp2 cells but less in the Wisp2 gene disrupted cells. In summary, Wisp2 promotes the homing of BMSCs through Cxcr4 related signaling during liver repair in rats.

Excess of dietary montmorillonite impairs growth performance, liver function, and antioxidant capacity in starter pigs.

Montmorillonite (MMT) is widely used as a mycotoxin adsorbent in animal feeds, but its safety remains unclear. This study was conducted to investigate the safety of MMT supplementation in diets fed to starter pigs. A total of 120 32-d-old piglets (initial weight, 8.0 ± 0.9 kg) were randomly allotted into dietary treatments with graded MMT levels (0 [FS 0], 0.5% [FS 0.5], 1.0% [FS 1.0], 2.5% [FS 2.5], and 5.0% [FS 5.0]) with 6 replicate pens per treatment and 4 pigs per pen. All diets were fed for 28 d. As the MMT level increased, ADG and G:F changed in a linear and quadratic manner, while ADFI was linearly decreased ( > 0.05). Compared with FS 0, ADG, ADFI, and G:F of pigs in FS 1.0 increased ( < 0.05). However, the ADFI in pigs of FS 5.0 was lower than that in pigs of FS 0 ( < 0.05). The relative liver weight activities of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) changed in a linear and quadratic manner ( < 0.05). Compared with FS 0, pigs in FS 2.5 and FS 5.0 had a greater serum ALT ( < 0.05), while AST activity significantly increased in pigs of FS 5.0 ( < 0.05). Dietary MMT supplementation decreased serum Mg content in a linear and quadratic manner ( < 0.05), while Zn and Cu contents were linearly decreased ( < 0.05). Serum Zn and Cu contents of pigs in FS 0.5, FS 2.5, and FS 5.0 groups were lower than those in the control. Pigs fed with 2.5% and 5% MMT showed hepatic histopathological changes, including swelling, granular and vesicular degeneration, and apparent vacuolar degeneration. In addition, the content of serum total antioxidant capacity (T-AOC) and activity of glutathione peroxidase (GSH-PX) decreased in a linear and quadratic manner ( < 0.05). Compared to the control, 5.0% MMT significantly increased piglets' serum malondialdehyde (MDA) concentration and decreased GSH-PX activity ( < 0.05). T-AOC concentration in the pigs fed 2.5% and 5.0% MMT was lower than that in the control group ( < 0.05). Serum superoxide dismutase (SOD) activity changed in a quadratic manner ( < 0.05). Piglets in FS 1.0 showed a higher SOD activity when compared with the control ( < 0.05). These results indicate that supplementation of MMT higher than 1.0% can negatively affect liver structure and serum mineral content, and 5.0% MMT supplementation would also decrease feed intake, aggravate liver damage, and reduce the antioxidant capacity of starter pigs. Therefore, excess supplementation of MMT is not safe in starter pigs.

Possible Involvement of Nitric Oxide in Enhanced Liver Injury and Fibrogenesis during Cholestasis in Cytoglobin-deficient Mice

This study clarified the role of Cygb, the fourth globin in mammals originally discovered in rat hepatic stellate cells (HSCs), in cholestatic liver disease. Bile duct ligation (BDL) augmented inflammatory reactions as revealed by increased infiltrating neutrophils, CD68+-macrophages, and chemokine expression in Cygb−/− mice. In these mice, impairment of bile canalicular indicated by the loss of CD10 expression, down-regulation of bile salt transporters, increased total bile acid, and massive apoptotic and necrotic hepatocytes occurred with the release of cytochrome c, activation of caspase 3, resulting in reduced animal survival compared to wild-type mice. In Cygb−/− mouse liver, all of NO metabolites and oxidative stress were increased. Treatment with NO inhibitor restrained all above phenotypes and restored CD10 expression in BDL Cygb−/− mice, while administration of NO donor aggravated liver damage in BDL-wild type mice to the same extent of BDL-Cygb−/− mice. N-acetylcysteine administration had a negligible effect in all groups. In mice of BDL for 1–3 weeks, expression of all fibrosis-related markers was significantly increased in Cygb−/− mice compared with wild-type mice. Thus, Cygb deficiency in HSCs enhances hepatocyte damage and inflammation in early phase and fibrosis development in late phase in mice subjected to BDL, presumably via altered NO metabolism.

Epidermal growth factor signaling protects from cholestatic liver injury and fibrosis

We have demonstrated that the signal transducer and activator of transcription 3 (STAT3) protects from cholestatic liver injury. Specific ablation of STAT3 in hepatocytes and cholangiocytes (STAT3∆hc) aggravated liver damage and fibrosis in the Mdr2−/− (multidrug resistance 2) mouse model for cholestatic disease. Upregulation of bile acid biosynthesis genes and downregulation of epidermal growth factor receptor (EGFR) expression were observed in STAT3∆hc Mdr2−/− mice but the functional consequences of these processes in cholestatic liver injury remained unclear. Here, we show normal canalicular architecture and bile flow but increased amounts of bile acids in the bile of STAT3∆hc Mdr2−/− mice. Moreover, STAT3-deficient hepatocytes displayed increased sensitivity to bile acid-induced apoptosis in vitro. Since EGFR signaling has been reported to protect hepatocytes from bile acid-induced apoptosis, we generated mice with hepatocyte/cholangiocyte-specific ablation of EGFR (EGFR∆hc) and crossed them to Mdr2−/− mice. Importantly, deletion of EGFR phenocopied deletion of STAT3 and led to aggravated liver damage, liver fibrosis, and hyperproliferation of K19+ cholangiocytes. Our data demonstrate hepatoprotective functions of the STAT3-EGFR signaling axis in cholestatic liver disease.Key messageSTAT3 is a negative regulator of bile acid biosynthesis.STAT3 protects from bile acid-induced apoptosis and regulates EGFR expression.EGFR signaling protects from cholestatic liver injury and fibrosis.

Cholesterol metabolism and non-alcoholic steatohepatitis

The disease spectrum of non-alcoholic fatty liver disease (NAFLD) includes non-alcoholic simple fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), as well as liver cirrhosis and hepatocellular carcinoma, with the most serious type being NASH. The morbidity of NAFLD is seeing an increase year by year in the world, and it is a common cause of chronic hepatic disease and lacks effective treatment. The pathogenesis of NASH is still unknown, and the "two-hit" hypothesis was used to explain the mechanism of NASH. Recent research has found that cholesterol metabolism is closely related to the pathogenesis and severity of NASH. The validity of the "two-hit" hypothesis has been recently challenged, which gives rise to "multi-parallel hit" hypothesis. Cholesterol affects membrane fluidity and membrane protein function through genetic factors, and it can also induce unfolded protein response, and generate toxic oxysterol. Free cholesterol can activate hepatic Kupffer and stellate cells to produce inflammatory cytokines and collagen. The formation of cholesterol crystallization and crown-like structures can damage liver cells and activate Kupffer cells. The above processes can all aggravate liver damage, thus accelerating the development and making the clinical manifestations of NASH even worse. In the present review we summarize the association between cholesterol metabolism and pathogenesis of NASH.

Liver Damage in Patients with HCV/HIV Coinfection Is Linked to HIV-Related Oxidative Stress.

HIV infection aggravates the progression of liver damage in HCV-coinfected patients, with the underlying pathogenesis being multifactorial. Although high level of oxidative stress has been observed frequently in patients infected with HIV or HCV, the status of oxidative stress in HIV/HCV coinfection and its contribution to HCV liver damage have not been determined. This study involved 363 HBsAg-negative, anti-HCV-positive former blood donors recruited from a village in central China in July 2005; of these, 140 were positive for HIV. Of these 363 subjects, 282 were successfully followed up through July 2009. HIV/HCV-coinfected subjects had higher rates of end-stage liver disease-related death than those monoinfected with HCV. Liver ultrasound manifestations were poor in HIV-positive than in HIV-negative individuals, in both chronic HCV carriers and those with resolved HCV. Serum concentrations of total glutathione (tGSH), malondialdehyde (MDA), glutathione peroxidase (GSH-Px), GSSG, and reduced GSH were higher in HIV-positive than HIV-negative subjects. GSSG concentrations were higher in HIV-infected subjects with abnormal ALT/AST levels than in those with normal ALT/AST levels and were associated with poorer liver ultrasound manifestations. These finding indicated that HIV infection accelerated HCV-associated liver damage in HIV/HCV-coinfected individuals. Increased oxidative stress, induced primarily by HIV coinfection, may contribute to aggravated liver damage.

Superoxide Dismutase 1 Protects Hepatocytes from Type I Interferon-Driven Oxidative Damage

SummaryTissue damage caused by viral hepatitis is a major cause of morbidity and mortality worldwide. Using a mouse model of viral hepatitis, we identified virus-induced early transcriptional changes in the redox pathways in the liver, including downregulation of superoxide dismutase 1 (Sod1). Sod1−/− mice exhibited increased inflammation and aggravated liver damage upon viral infection, which was independent of T and NK cells and could be ameliorated by antioxidant treatment. Type I interferon (IFN-I) led to a downregulation of Sod1 and caused oxidative liver damage in Sod1−/− and wild-type mice. Genetic and pharmacological ablation of the IFN-I signaling pathway protected against virus-induced liver damage. These results delineate IFN-I mediated oxidative stress as a key mediator of virus-induced liver damage and describe a mechanism of innate-immunity-driven pathology, linking IFN-I signaling with antioxidant host defense and infection-associated tissue damage.Video

Damage to Wistar rat livers after hypo-fractionated radiation and oxaliplatin

Abstract Objective The purpose of this study was to clarify whether hypo-fractionated radiation therapy combined with oxaliplatin can aggravate liver damage, in order to determine its safety for clinical application. Methods Eighty Wistar rats were randomly divided into four groups: the control group, the chemotherapy treatment group, the radiation treatment group, and the concurrent chemoradiotherapy group. The rats’ liver tissues were then collected for histological evaluation at the first, second, fourth, sixth, and eight week after irradiation. The tissues were histologically evaluated using hematoxylin and eosin staining, and immunohistochemistry to analyze the expression of Bcl-2 and Bax. Results Histological examination revealed swollen hepatocellular cells in the experimental groups, with visible liver degeneration and necrosis. Alanine aminotransferase and aspartate aminotransferase levels were significantly different between the groups (F = 85.869 and 214.663; P &lt; 0.001). The intra-group expressions of Bcl-2 and Bax were also significantly different between each time point (F = 6.047 and 43.344; P &lt; 0.05). Bax expression was significantly different between each group (F = 8.122; P &lt; 0.05), although no inter-group differences were observed for Bcl-2 expression (F = 0.808; P &gt; 0.05). Conclusion Chemoradiotherapy may aggravate liver injury, possible via overexpression of Bcl-2 and reduced expression of Bax. Therefore, this treatment should be used carefully in the clinic.

Secreted IL-1α promotes T-cell activation and expansion of CD11b(+) Gr1(+) cells in carbon tetrachloride-induced liver injury in mice.

Interleukin-1α is mainly expressed on the cell membrane, but can also be secreted during inflammation. The roles of secreted and membrane IL-1α in acute liver inflammation are still not known. Here, we examined the functions of secreted and membrane IL-1α in a mouse model of carbon tetrachloride-induced acute liver injury. We show that secreted IL-1α aggravates liver damage and membrane IL-1α slightly protects mice from liver injury. Further studies showed that secreted IL-1α promotes T-cell activation. It also increased the expansion of CD11b(+) Gr1(+) myeloid cells, which may serve as a negative regulator of acute liver inflammation. Moreover, secreted IL-1α induced IL-6 production from hepatocytes. IL-6 neutralization reduced the proliferation of CD11b(+) Gr1(+) myeloid cells in vivo. CCL2 and CXCL5 expression was increased by secreted IL-1α in vitro and in vivo. Antagonists of the chemokine receptors for CCL2 and CXCL5 significantly reduced the migration of CD11b(+) Gr1(+) myeloid cells. These results demonstrate that secreted and membrane IL-1α play different roles in acute liver injury. Secreted IL-1α could promote T-cell activation and the recruitment and expansion of CD11b(+) Gr1(+) myeloid cells through induction of CCL2, CXCL5, and IL-6. The controlled release of IL-1α could be a critical regulator during acute liver inflammation.

Regulation of mice liver regeneration by early growth response-1 through the GGPPS/RAS/MAPK pathway

Background & AimsLiver regeneration (LR) consists of a series of complicated processes in which several transcription factors play important roles. Among them, the early growth response 1 gene (EGR-1) is rapidly induced in response to liver resection. Previous studies have shown that EGR-1−/− mice exhibit delayed hepatocellular mitotic progression after partial hepatectomy (PH). The mechanism underlying the EGR-1 regulated LR is still unknown. Our aim is to elucidate the underlying mechanism. MethodsMice infected with adenoviral vectors expressing GFP, EGR-1 or dominant negative EGR-1 (dnEGR-1) were subjected to 2/3 PH. The serum starvation recovery cell model was chosen to mimic the regeneration process for the in vitro studies. Cell proliferation and signaling pathways downstream of geranylgeranyl diphosphate synthase (GGPPS) were examined in the regenerating liver and serum starvation recovery cell model. ResultsLoss of function of EGR-1 significantly inhibited liver recovery and the expression of cyclin D1, cyclin E, and proliferating cell nuclear antigen (PCNA). The expression of GGPPS and the activity of the downstream RAS/MAPK pathway were inhibited in dnEGR-1-infected liver, which was consistent with the serum-induced cell model. In addition, loss of function of EGR-1 aggravated liver damage with increased serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels. ConclusionsEGR-1-induced GGPPS plays a vital role in the LR after PH through the RAS/MAPK signaling.

Updates in the research of portal vein thrombosis in patients with cirrhosis and portal hypertension after splenectomy

Portal vein thrombosis (PVT) is a severe complication in patients with cirrhosis and portal hypertension after splenectomy. PVT can aggravate liver damage, ischaemic intestinal necrosis and gastrointestinal bleeding. In recent years, numerous studies have been published on the risk factors, diagnosis, prevention and treatment of PVT. Imaging examination in patients could be done for early diagnosis of PVT and improve the prognosis of patients. Key words: Liver cirrhosis; Splenectomy; Venous thrombosis; Thrombosis, portal vein

Propargylglycine aggravates liver damage in LPS-treated rats: Possible relation of nitrosative stress with the inhibition of H2S formation

BackgroundHydrogen sulfide (H2S) is a naturally occurring gaseous transmitter, which may play important roles in normal physiology and disease. Here, we investigated the effect of endogenously formed H2S in the endotoxemic organ injury. MethodsMale Wistar rats were subjected to acute endotoxemia [Escherichia coli lipopolysaccharide (LPS) 20mgkg−1, intraperitoneally (ip)]. A group of animals was injected d,l-propargylglycine (PAG, 50mgkg−1, ip), an inhibitor of the H2S-synthesizing enzyme cystathionine-γ-lyase (CSE), 60min before LPS administration. Six hours after the LPS treatment, animals were sacrificed. Myeloperoxidase (MPO), dimethylarginine dimethylaminohydrolase (DDAH) activities and levels of nitrotyrosine and GSH were measured in the liver. Asymmetric dimethylarginine (ADMA) and arginine levels in both liver and plasma were determined using HPLC. ResultsLPS injections caused liver injury, as evidenced by the activities of serum aspartate aminotransferase and arginase. After LPS injections, increased arginine content and arginine/ADMA ratio were observed in the liver, together with significant decrements in both DDAH activity and GSH levels. Despite the accumulation of ADMA in the plasma, its level remained unchanged in the liver. PAG pretreatment aggravated the LPS-induced increase in the activities of MPO and serum enzymes. The most profound effect of PAG pretreatment was observed in nitrotyrosine levels in the liver, which were increased significantly as compared with the control and LPS-injected groups. ConclusionThese findings support the view that the suppression of nitrosative stress by endogenous H2S is one of the mechanisms to protect liver against endotoxemic injury.